Injectable flowable composition comprising buprenorphine

ABSTRACT

The present invention is directed to a buprenorphine sustained release delivery system capable of delivering buprenorphine, a metabolite, or a prodrug thereof for a duration of about 14 days to about 3 months. The buprenorphine sustained release delivery system includes a flowable composition and a solid implant for the sustained release of buprenorphine, a metabolite, or a prodrug thereof. The implant is produced from the flowable composition. The buprenorphine sustained release delivery system provides in situ 1-month and 3-month release profiles characterized by an exceptionally high bioavailability and minimal risk of permanent tissue damage and typically no risk of muscle necrosis.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/995,053 filed Jan. 13, 2016, allowed; which is a continuation of U.S.application Ser. No. 14/610,818 filed Jan. 30, 2015, issued as U.S. Pat.No. 9,272,044; which is a continuation of U.S. application Ser. No.13/836,134 filed Mar. 15, 2013, issued as U.S. Pat. No. 8,975,270; whichis a continuation-in-part of U.S. application Ser. No. 13/703,013 filedDec. 8, 2012, issued as U.S. Pat. No. 8,921,387; which is a Section 371U.S. National Stage of International Application No. PCT/GB2011/051057filed Jun. 6, 2011; which claims priority to United Kingdom ApplicationNo. GB 1009549.5 filed Jun. 8, 2010, all of which are herein fullyincorporated by reference.

FIELD OF THE INVENTION

This disclosure relates to a buprenorphine sustained release deliverysystem for treatment of conditions ameliorated by buprenorphinecompounds. The sustained release delivery system includes a flowablecomposition containing buprenorphine, a metabolite, or a prodrug thereofand an implant containing buprenorphine, a metabolite, or a prodrugthereof.

BACKGROUND OF THE INVENTION

Buprenorphine (also known as(2S)-2-[(−)-(5R,6R,7R,14S)-9α-cyclo-propyl-methyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-di-methylbutan-2-oland marketed under the trade names SUBUTEX® and SUBOXONE® (Indivior UKLimited) for relief of opioid addiction.

The chemical structure of buprenorphine is shown in Formula (1).

Buprenorphine is most often used to treat symptoms arising from opioidaddiction and for the long term relief of pain. Currently, thecommercial products are SUBUTEX™ and SUBOXONE™ marketed by RB PharmaInc. These products are in a tablet formulation and are intended todeliver therapeutic levels of buprenorphine for short periods of time ofup to several hours and are typically taken either buccally orsub-lingually. However, the patient is required to supplement this doseat regular intervals, and there are often issues with diversion inpatients with an opioid dependence problem. There is a need thereforefor a longer term, non-divertible method of administering buprenorphinewhich delivers a constant and effective dose of the active to thepatient over a period of up to 30 days, and which does not result in anunwanted accumulation of residual active in the patient's metabolism.

Various sustained release methods are employed in the pharmaceuticalindustry, for example, systems such as solid, biodegradable rods, ornondegradable reservoirs. These, however, typically require surgicalimplantation and furthermore, for the nondegradable delivery systems, asecond surgical procedure is required to remove the empty reservoir.

There is a continuing need to develop products providing increasedbioavailability of buprenorphine. In particular, there is a need todevelop sustained release formulations of buprenorphine that do notsuffer from low bioavailability, poor release kinetics, injection sitetoxicity, relatively large volume injections, and inconveniently shortduration of release.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a buprenorphine sustained releasedelivery system capable of delivering buprenorphine, a metabolite, or aprodrug thereof for a duration of about 14 days to about 3 months. Thebuprenorphine sustained release delivery system includes a flowablecomposition and a solid implant for the sustained release ofbuprenorphine, a metabolite, or a prodrug thereof. The implant isproduced from the flowable composition. The buprenorphine sustainedrelease delivery system provides in situ 1-month and 3-month releaseprofiles characterized by an exceptionally high bioavailability andminimal risk of permanent tissue damage and typically no risk of musclenecrosis.

In one embodiment, a buprenorphine sustained release delivery system isprovided. This delivery system includes a flowable composition and acontrolled, sustained release implant. The flowable compositionaccording to this embodiment comprises a biodegradable thermoplasticpolymer, a biocompatible, polar organic liquid, and buprenorphine, ametabolite, or a prodrug thereof. The flowable composition may betransformed into the implant by contact with water, body fluid, or otheraqueous medium. In one embodiment, the flowable composition is injectedinto the body whereupon it transforms in situ into the solid implant.

According to a first embodiment of the present invention, therefore,there is provided an injectable flowable composition comprising:

(a) at least one biodegradable thermoplastic polymer which is at leastsubstantially insoluble in body fluid;

(b) a biocompatible polar aprotic organic liquid which comprises anamide, an ester, a carbonate, a lactam, an ether, a sulfonyl, or anycombination thereof; which has a solubility in aqueous medium or bodyfluid ranging from insoluble to completely soluble in all proportions;and,

(c) 1 wt % to 10 wt % of buprenorphine, a metabolite, or a prodrugthereof;

wherein the composition is transformed in situ into a solid implant bycontact with water, body fluid or other aqueous medium.

The thermoplastic polymer of the flowable composition and implant is atleast substantially insoluble in an aqueous medium or body fluid, ortypically completely insoluble in those media. The thermoplastic polymermay be a homopolymer, a copolymer, or a terpolymer of repeatingmonomeric units linked by such groups as ester groups, anhydride groups,carbonate groups, amide groups, urethane groups, urea groups, ethergroups, esteramide groups, acetal groups, ketal groups, orthocarbonategroups, and any other organic functional group that can be hydrolyzed byenzymatic or hydrolytic reaction (i.e., is biodegradable by thishydrolytic action). The thermoplastic polymer may be a polyester thatmay be composed of units of about one or more hydroxycarboxylic acidresidues, or diol and dicarboxylic acid residues, wherein thedistribution of differing residues may be random, block, paired, orsequential. The polyester may be a combination of about one or morediols and about one or more dicarboxylic acids. The hydroxy carboxylicacid or acids may also be in the form of dimers.

When the biodegradable thermoplastic polymer is a polyester, thepolyesters include, for example, a polylactide, a polyglycolide, apolycaprolactone, a copolymer thereof, a terpolymer thereof, or anycombination thereof, optionally incorporating a third mono-alcohol orpolyol component. More preferably, the biodegradable thermoplasticpolyester is a polylactide, a polyglycolide, a copolymer thereof, aterpolymer thereof, or a combination thereof, optionally incorporating athird mono-alcohol or polyol component. Preferably the polyester is a50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5poly(DL-lactide-co-glycolide) having a carboxy terminal group, or is a50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5poly(DL-lactide-co-glycolide) without a carboxy terminal group. Morepreferably, the suitable biodegradable thermoplastic polyester is about50/50 poly(lactide-co-glycolide) (hereinafter PLG) having a carboxyterminal group or is a 75/25 or a 85/15 PLG with a carboxy terminalgroup or such a PLG formulated with about one or more mono-alcohol orpolyol units. When a mono-alcohol or polyol is incorporated into thepolyester, the mono-alcohol or polyol constitutes a third covalentcomponent of the polymer chain. When a mono-alcohol is incorporated, thecarboxy terminus of the polyester is esterified with the mono-alcohol.When a polyol is incorporated, it chain extends and optionally branchesthe polyester. The polyol functions as a polyester polymerization pointwith the polyester chains extending from multiple hydroxyl moieties ofthe polyol, and those hydroxyl moieties are esterified by a carboxylgroup of the polyester chain. For an embodiment employing a diol, thepolyester is linear with polyester chains extending from both esterifiedhydroxy groups. For an embodiment employing a triol or higher polyol,the polyester may be linear or may be branched with polyester chainsextending from the esterified hydroxy groups. Suitable polyols include,for example, aliphatic and aromatic diols, saccharides such as glucose,lactose, maltose, sorbitol, triols such as glycerol, fatty alcohols, andthe like, tetraols, pentaols, hexaols, and the like.

The biodegradable thermoplastic polymer can be present in any suitableamount, provided the biodegradable thermoplastic polymer is at leastsubstantially insoluble in aqueous medium or body fluid. Preferably thebiodegradable thermoplastic polyester is present in about 5 wt. % toabout 95 wt. % of the flowable composition, or is present in about 15wt. % to about 70 wt. % of the flowable composition, or is present inabout 25 wt. % to about 50 wt. % of the flowable composition.

Preferably, the biodegradable thermoplastic polymer has an averagemolecular weight of about 5,000 Daltons (Da) to about 40,000 Daltons, ormore preferably about 10,000 Daltons to about 20,000 Daltons.

The flowable composition also includes a biocompatible, polar organicliquid. The biocompatible polar liquid can be an amide, an ester, acarbonate, an ether, a sulfonyl, or any other organic compound that isliquid at ambient temperature and is polar. The organic liquid may bevery slightly soluble to completely soluble in all proportions in bodyfluid. While the organic liquid generally should have similar solubilityprofiles in aqueous medium and body fluid, body fluid is typically morelipophilic than aqueous medium. Consequently, some organic liquids thatare insoluble in aqueous medium should be at least slightly soluble inbody fluid. These examples of organic liquid are included within thedefinition of organic liquids.

Preferably, the organic liquid comprises N-methyl-2-pyrrolidone,2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylenecarbonate, caprolactam, triacetin, or any combination thereof. Morepreferably, the organic liquid is N-methyl-2-pyrrolidone. Preferably,the polar organic liquid is present in about 10 wt. % to about 90 wt. %of the composition or is present in about 30 wt. % to about 70 wt. % ofthe composition.

The buprenorphine, a metabolite, or a prodrug thereof is present inabout 1 wt % to about 30 wt % of the flowable composition; preferablybetween 5 wt % and 25 wt %; more preferably between 8 wt % and 22 wt %.

In one embodiment, the buprenorphine, a metabolite, or a prodrug thereofin the flowable composition may be in the neutral or free base form. Ina further embodiment, the buprenorphine, a metabolite, or a prodrugthereof in the flowable composition may be in the form of a salt and thesalt gegenion may be derived from a pharmaceutically acceptable organicor inorganic acid, or the gegenion may be a polycarboxylic acid.

In a further preference, the weight ratio of the buprenorphine, ametabolite, or a prodrug thereof to the biodegradable thermoplasticpolymer(s) is between 0.001:1 and 1.5:1.

The flowable composition is formulated as an injectable delivery system.The flowable composition preferably has a volume of about 0.10 mL toabout 2.0 mL or preferably about 0.20 mL to about 1.0 mL. The injectablecomposition is preferably formulated for administration about once permonth, about once per three months, or about once per four months, toabout once per six months. Preferably, the flowable composition is aliquid or a gel composition, suitable for injection into a patient. Theflowable composition may have the property of production of minimaltissue necrosis when injected subcutaneously.

Excipients, release modifiers, plasticizers, pore forming agents,gelation liquids, non-active extenders, and other ingredients may alsobe included within the buprenorphine sustained release delivery system.Upon administration of the flowable composition, some of theseadditional ingredients, such as gelation liquids and release modifiersshould remain with the implant, while others, such as pore formingagents should separately disperse and/or diffuse along with the organicliquid.

In one embodiment, a method is provided for forming a flowablecomposition for use as a controlled release implant. The method includesmixing, in any order, a biodegradable thermoplastic polymer, abiocompatible polar aprotic liquid, and buprenorphine, a metabolite, ora prodrug thereof. The biodegradable thermoplastic polymer may be atleast substantially insoluble in aqueous medium or body fluid. Theseingredients, their properties, and preferred amounts are as disclosedabove. The mixing is performed for a sufficient period of time effectiveto form the flowable composition for use as a controlled releaseimplant. Preferably, the biocompatible thermoplastic polymer and thebiocompatible polar aprotic organic liquid are mixed together to form amixture and the mixture is combined with the buprenorphine, ametabolite, or a prodrug thereof to form the flowable composition.Preferably, the flowable composition is a solution or dispersion,especially preferably a solution, of the buprenorphine, a metabolite, ora prodrug thereof and biodegradable thermoplastic polymer in the organicliquid. The flowable composition preferably includes an effective amountof a biodegradable thermoplastic polymer, an effective amount of abiocompatible polar aprotic organic liquid, and an effective amount ofbuprenorphine, a metabolite, or a prodrug thereof. These ingredients,the preferred ingredients, their properties, and preferred amounts areas disclosed above.

In one embodiment, a biodegradable implant formed in situ, in a patientis provided, by the steps including: injecting a flowable compositionincluding a biodegradable thermoplastic polymer that is at leastsubstantially insoluble in body fluid, a biocompatible polar aproticorganic liquid; and buprenorphine, a metabolite, or a prodrug thereofinto the body of the patient, and allowing the biocompatible polaraprotic liquid to dissipate to produce a solid or gel biodegradableimplant. The flowable composition includes an effective amount of thebiodegradable thermoplastic polymer, an effective amount of thebiocompatible polar aprotic liquid, and an effective amount ofbuprenorphine, a metabolite, or a prodrug thereof and the solid implantreleases an effective amount of buprenorphine, a metabolite, or aprodrug thereof over time as the solid implant biodegrades in thepatient and optionally the patient is a human.

In one embodiment, a method is provided of forming a biodegradableimplant in situ, in a living patient. The method includes injecting theflowable composition including a biodegradable thermoplastic polymerthat is at least substantially insoluble in body fluid, a biocompatiblepolar aprotic organic liquid, and buprenorphine, a metabolite, or aprodrug thereof within the body of a patient and allowing thebiocompatible polar aprotic organic liquid to dissipate to produce asolid biodegradable implant. Preferably, the biodegradable solid implantreleases an effective amount of buprenorphine, a metabolite, or aprodrug thereof by diffusion, erosion, or a combination of diffusion anderosion as the solid implant biodegrades in the patient.

In one embodiment, a method is provided of treating or preventingmammalian diseases that are ameliorated, cured, or prevented bybuprenorphine, a metabolite, or a prodrug thereof. The method includesadministering, to a patient (preferably a human patient) in need of suchtreatment or prevention, an effective amount of a flowable compositionincluding a biodegradable thermoplastic polymer that is at leastsubstantially insoluble in body fluid, a biocompatible polar aproticorganic liquid, and buprenorphine, a metabolite, or a prodrug thereof.

In a further embodiment, a kit is provided. In a preferred form of thisembodiment, the kit includes a first container and a second container.The first container includes a composition of the biodegradablethermoplastic polymer and the biocompatible polar aprotic organicliquid. The biodegradable thermoplastic polymer may be at leastsubstantially insoluble in aqueous medium or body fluid. The secondcontainer includes buprenorphine, a metabolite, or a prodrug thereof.These ingredients, their properties, and preferred amounts are asdisclosed above. Preferably, the first container is a syringe and thesecond container is a syringe. The kit can preferably include, forexample, instructions. Preferably, the first container can be connectedto the second container. More preferably, the first container and thesecond container are each configured to be directly connected to eachother.

In a further form of this embodiment, the kit comprises a single syringecomprising a composition comprising a biodegradable thermoplasticpolymer that is at least substantially insoluble in a body fluid, abiocompatible polar aprotic liquid and buprenorphine, a metabolite, or aprodrug thereof.

In a further embodiment, a solid implant is provided. The solid implantis composed of at least the biocompatible thermoplastic polymer andbuprenorphine, a metabolite, or a prodrug thereof and is substantiallyinsoluble in body fluid. The biodegradable thermoplastic polymer may beat least substantially insoluble in aqueous medium or body fluid. Whilebuprenorphine, a metabolite, or a prodrug thereof itself has at leastsome solubility in body fluid, its isolation within the substantiallyinsoluble implant allows for its slow, sustained release into the body.

The solid implant has a solid matrix or a solid microporous matrix. Thematrix can be a core surrounded by a skin. The implant may be solid andmicroporous. When microporous, the core preferably contains pores ofdiameters from about 1 to about 1000 microns. When microporous, the skinpreferably contains pores of smaller diameters than those of the corepores. In addition, the skin pores are preferably of a size such thatthe skin is functionally non-porous in comparison with the core. Thesolid implant can optionally include, for example, one or morebiocompatible organic substances which may function as an excipient asdescribed above, or which may function as a plasticizer, a sustainedrelease profile modifier, emulsifier, and/or isolation carrier forbuprenorphine, a metabolite, or a prodrug thereof. The biocompatibleorganic liquid may also serve as an organic substance of the implantand/or may provide an additional function such as a plasticizer, amodifier, an emulsifier, or an isolation carrier. There may be two ormore organic liquids present in the flowable composition such that theprimary organic liquid acts as a mixing, solubilizing, or dispersingagent, and the supplemental organic liquid or liquids provide additionalfunctions within the flowable composition and the implant.Alternatively, there may be one organic liquid which at least may act asa mixing, solubilizing, or dispersing agent for the other components,and may provide additional functions as well. As second or additionalcomponents, additional kinds of biodegradable organic liquids typicallyare combined with the flowable composition and may remain with theimplant as the administered flowable composition coagulates.

When serving as a plasticizer, the biocompatible organic substanceprovides such properties as flexibility, softness, moldability, and drugrelease variation to the implant. When serving as a modifier, thebiocompatible organic substance also provides the property ofbuprenorphine release variation to the implant. Typically, theplasticizer increases the rate of buprenorphine, a metabolite, or aprodrug thereof release while the modifier slows the rate ofbuprenorphine, a metabolite, or a prodrug thereof release. Also, therecan be structural overlap between these two kinds of organic substancesfunctioning as plasticizers and rate modifiers.

When serving as an emulsifier, the biocompatible organic substance atleast in part enables a uniform mixture of the buprenorphine, ametabolite, or a prodrug thereof within the flowable composition andwithin the implant. When serving as an isolation carrier, thebiocompatible organic substance should function to encapsulate, isolate,or otherwise surround molecules or nanoparticles of the buprenorphine, ametabolite, or a prodrug thereof so as to prevent its burst at least inpart, and to isolate the buprenorphine, a metabolite, or a prodrugthereof from degradation by other components of the flowable compositionand implant.

The amount of biocompatible organic substance optionally remaining inthe solid or gel implant is preferably minor, such as from about 0 wt. %(or an almost negligible amount) to about 20 wt. % of the composition.In addition, the amount of biocompatible organic substance optionallypresent in the solid or gel implant preferably decreases over time.

The solid implant may also include, for example, a biocompatible organicliquid that is very slightly soluble to completely soluble in allproportions in body fluid and at least partially dissolves at least aportion of the thermoplastic polyester, and optionally the amount ofbiocompatible organic liquid is less than about 5 wt. % of the totalweight of the implant, and optionally the amount of biocompatibleorganic liquid decreases over time.

The solid implant may also include, for example, a core that containspores of diameters from about 1 to about 1000 microns, and optionallythe skin contains pores of smaller diameters than those of the corepores, and optionally the skin pores are of a size such that the skin isfunctionally non-porous in comparison with the core.

In one embodiment, a flowable composition having an initial limitedburst followed by a substantially linear release profile, then a periodof gradually slower release. Preferably, the linear release profilelasts for 28 days.

In one embodiment, a method is provided for treatment of a patienthaving a medical condition including administering to the patient aneffective amount of buprenorphine, a metabolite, or a prodrug thereof incombination with an at least substantially water-insoluble biodegradablethermoplastic polymer and a biocompatible, polar, aprotic organicliquid, wherein the medical condition comprises opioid addiction andchronic pain. This method of treatment may include, for example,combination therapy with another known pharmaceutical compounddesignated for treatment of the malcondition.

Preferably the flowable composition is formulated for administrationabout once per month, or about once per three months, or about once perfour months, or about once per six months.

In one embodiment, a method is provided for treating a patient having amedical condition comprising administering to the patient a flowablecomposition to provide a biodegradable implant comprising buprenorphine,a metabolite, or a prodrug thereof and a biodegradable polymer, whereinthe implant releases delivers therapeutically effective dosage fromabout 0.1 to about 10 milligrams (mg) of buprenorphine, a metabolite, ora prodrug thereof per day, or preferably from about 1 to about 5milligrams (mg) of buprenorphine, a metabolite, or a prodrug thereof perday. The therapeutically effective dosage of buprenorphine, ametabolite, or a prodrug thereof may be achieved within about five daysafter administration of the implant, or preferably, within about one dayafter administration of the implant. The therapeutically effectivedosage of buprenorphine, a metabolite, or a prodrug thereof may bedelivered for at least about 15 days after administration of theimplant, or preferably for at least about 28 days after administrationof the implant, or preferably for at least about 45 days afteradministration of the implant, or preferably for at least about 60 daysafter administration of the implant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the 49 day release of buprenorphine from selectedATRIGEL® formulations of buprenorphine hydrochloride subcutaneouslyinjected in rats.

FIG. 2 illustrates the 35 day release of buprenorphine from selectedATRIGEL® formulations of buprenorphine free base subcutaneously injectedin rats.

FIG. 3 illustrates the 35 day plasma concentration levels ofbuprenorphine from further selected ATRIGEL® formulations ofbuprenorphine free base subcutaneously injected in rats.

FIG. 4 illustrates the 180 day plasma concentration levels of activebuprenorphine in dogs subcutaneously injected with anATRIGEL®/(buprenorphine hydrochloride) formulation.

FIG. 5 illustrates the 195 day release of buprenorphine from selectedATRIGEL® formulations in dogs subcutaneously injected with anAtrigel/(buprenorphine free base) formulation.

FIG. 6. illustrates the mean plasma buprenorphine levels aftersubcutaneous injection of a buprenorphine free base ATRIGEL® in beagles.

FIG. 7. illustrates the buprenorphine release profiles aftersubcutaneous injection of buprenorphine free base ATRIGEL® formulationsin rats.

DEFINITIONS

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, a reference to “a formulation” includes a plurality of suchformulations, so that a formulation of compound X includes formulationsof compound X.

As used herein, the term “acceptable salts” refer to derivatives whereinthe parent compound is modified by making acid or base salts thereof.Suitable acceptable salts include, but are not limited to, mineral ororganic acid salts of basic residues such as amines; alkali or organicsalts of acidic residues such as carboxylic acids; and the like. Theacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric, and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl acetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methane-sulfonic, ethane disulfonic, oxalic,isethionic, and the like. Specifically, the acceptable salts caninclude, for example, those salts that naturally occur in vivo in amammal.

As used herein, the term “biocompatible” means that the material,substance, compound, molecule, polymer, or system to which it appliesshould not cause severe toxicity, severe adverse biological reaction, orlethality in an animal to which it is administered at reasonable dosesand rates.

As used herein, the term “biodegradable” means that the material,substance, compound, molecule, polymer, or system is cleaved, oxidized,hydrolyzed, or otherwise broken down by hydrolytic, enzymatic, oranother mammalian biological process for metabolism to chemical unitsthat can be assimilated or eliminated by the mammalian body.

As used herein, the term “bioerodable” means that the material,substance, compound, molecule, polymer, or system is biodegraded ormechanically removed by a mammalian biological process so that newsurface is exposed.

As used herein, average molecular weight is the weight average molecularweight of a polymer as determined by gel permeation chromatography (alsoknown as GPC or size exclusion chromatography (SEC)) usingtetrahydrofuran (THF) as the solvent and using a molecular weightcalibration curve using polystyrene standards.

As used herein, the term “therapeutically effective amount” is intendedto include an amount of buprenorphine, a metabolite, or a prodrugthereof, a pharmaceutically acceptable salt thereof, a derivativethereof, or any combination of those useful to treat or prevent theunderlying disorder or disease, or to treat the symptoms associated withthe underlying disorder or disease in a host. Synergy, as described, forexample, by Chou and Talalay, Adv. Enzyme Regul. 22, 27-55 (1984),occurs when the effect of buprenorphine, a metabolite, or a prodrugthereof, a pharmaceutically acceptable salt thereof, or a derivativethereof when administered in combination is greater than the additiveeffect of the buprenorphine, a metabolite, or a prodrug thereof,pharmaceutically acceptable salt thereof, or a derivative thereof whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at suboptimal concentrations of thebuprenorphine, a metabolite, or a prodrug thereof, a pharmaceuticallyacceptable salt thereof, or derivative thereof. Synergy can be in termsof lower cytotoxicity, increased activity, or some other beneficialeffect of the combination compared with the individual components.

As used herein, the term “flowable” refers to the ability of the“flowable” composition to be transported under pressure into the body ofa patient. For example, the flowable composition can have a lowviscosity like water, and be injected with the use of a syringe, beneaththe skin of a patient. The flowable composition can alternatively have ahigh viscosity as in a gel and can be placed into a patient through ahigh pressure transport device such as a high pressure syringe, cannula,needle, and the like. The ability of the composition to be injected intoa patient should typically depend upon the viscosity of the composition.The composition should therefore have a suitable viscosity ranging fromlow like water to high like a gel, such that the composition can beforced through the transport device (e.g., syringe) into the body of apatient.

As used herein, the term “gel” refers to a substance having agelatinous, jelly-like, or colloidal properties. See, e.g., CONCISECHEMICAL AND TECHNICAL DICTIONARY, 4th Edition, Chemical Publishing Co.,Inc., p. 567, New York, N.Y. (1986).

As used herein, the term “liquid” refers to a substance that undergoescontinuous deformation under a shearing stress. See, e.g., CONCISECHEMICAL AND TECHNICAL DICTIONARY, 4th Edition, Chemical Publishing Co.,Inc., p. 707, New York, N.Y. (1986).

As used herein, the term “patient” refers to a warm-blooded animal, andpreferably a mammal, such as, for example, a cat, dog, horse, cow, pig,mouse, rat, or primate, including a human. As used herein, the term“polymer” refers to a molecule of one or more repeating monomericresidue units covalently bonded together by one or more repeatingchemical functional groups. The term includes all polymeric forms suchas linear, branched, star, random, block, graft, and the like. Itincludes homopolymers formed from a single monomer, copolymer formedfrom two or more monomers, terpolymers formed from three or morepolymers, and polymers formed from more than three monomers. Differingforms of a polymer may also have more than one repeating, covalentlybonded functional group. The term may also refer to substantially linearpolyesters, also referred to herein as “PLG copolymers,” predominantlyformed of monomeric lactate and glycolate hydroxyacids, or lactide andglycolide dimeric hydroxyacids, and include, for example, compositionsreferred to in the art as poly(lactate-glycolate),poly(lactate(co)glycolate), poly(lactide-glycolide), poly(lactide(co)glycolide), PLG, PLGH, and the like, with the understanding thatadditional moieties may be included, such as core/initiator groups (forexample, diols, hydroxyacids, and the like), capping groups (forexample, esters of terminal carboxyl groups, and the like) and otherpendant groups or chain extension groups covalently linked to or withina polyester backbone, including groups that cross-link the substantiallylinear polyester molecular chains, without departing from the meaningassigned herein. PLG copolymers, as the term is used herein, includesmolecular chains with terminal hydroxyl groups, terminal carboxyl groups(i.e., acid-terminated, sometimes termed PLGH) and terminal ester groups(i.e., capped).

As used herein, the term “polyester” refers to polymers containingmonomeric repeats, at least in part, of the linking group: —OC(═O)— or—C(═O)O—.

As used herein, the terms “skin” and “core” of a skin and core matrixmean that a cross section of the matrix should present a discernabledelineation between an outer surface and the inner portion of thematrix. The outer surface is the skin and the inner portion is the core.As used herein, the term “thermoplastic” as applied to a polymer meansthat the polymer repeatedly should melt upon heating and should solidifyupon cooling. It signifies that no or a slight degree of cross-linkingbetween polymer molecules is present. It is to be contrasted with theterm “thermoset” which indicates that the polymer should set orsubstantially cross-link upon heating or upon application of a similarreactive process and should no longer undergo melt-solidification cyclesupon heating and cooling.

As used herein, the terms “treating,” “treat,” or “treatment” includes(i) preventing a pathologic condition (e.g., schizophrenia) fromoccurring (e.g., prophylaxis); (ii) inhibiting the pathologic condition(e.g., schizophrenia) or arresting its development; and (iii) relievingthe pathologic condition (e.g., relieving the symptoms associated withschizophrenia).

DESCRIPTION OF THE INVENTION

The present invention is directed to a buprenorphine sustained releasedelivery system. The sustained release delivery system includes aflowable composition and a solid implant. The delivery system providesan in situ sustained release of buprenorphine, a metabolite, or aprodrug thereof. The flowable composition accomplishes the sustainedrelease through its use to produce the implant. The implant has a lowimplant volume and provides a long term delivery of buprenorphine, ametabolite, or a prodrug thereof. The flowable composition enablessubcutaneous formation of the implant in situ and causes little or notissue necrosis. The in situ implant provides therapeutic plasmabuprenorphine, a metabolite, or a prodrug thereof levels immediatelyafter injection and maintains steady-state plasma levels from four tosix weeks.

Another advantage of one embodiment includes a simple manufacturingprocess and delivery system. For example, the buprenorphine, ametabolite, or a prodrug thereof is filled into a syringe, the syringeis sealed, and the entire drug substance syringe is terminallysterilized by gamma irradiation. The biodegradable polymer used isdissolved in N-methyl-2-pyrrolidinone and filled in a second syringe.The syringe is sealed and the delivery system is terminally sterilizedby gamma irradiation. At the time of injection, the syringes are coupledthrough the luer-lock connection and the product is constituted bycycling the components between the two syringes. In this way, the drugis incorporated into the delivery system and very little is lost to thedevice.

The flowable composition is a combination of a biodegradable, at leastsubstantially water-insoluble thermoplastic polymer, a biocompatiblepolar aprotic organic liquid and buprenorphine, a metabolite, or aprodrug thereof. The polar, aprotic organic liquid has a solubility inbody fluid ranging from practically insoluble to completely soluble inall proportions. Preferably, the thermoplastic polymer is athermoplastic polyester of about one or more hydroxycarboxylic acids orabout one or more diols and dicarboxylic acids. Especially preferably,the thermoplastic polymer is a polyester of about one or morehydroxylcarboxyl dimers such as lactide, glycolide, dicaprolactone, andthe like.

The specific and preferred biodegradable thermoplastic polymers andpolar aprotic solvents; the concentrations of thermoplastic polymers,polar aprotic organic liquids, and buprenorphine, a metabolite, or aprodrug thereof; the molecular weights of the thermoplastic polymer; andthe weight or mole ranges of components of the solid implant describedherein are exemplary. They do not exclude other biodegradablethermoplastic polymers and polar aprotic organic liquids; otherconcentrations of thermoplastic polymers, polar aprotic liquids, andbuprenorphine, a metabolite, or a prodrug thereof; other molecularweights of the thermoplastic polymer; and other components within thesolid implant.

In one embodiment, a flowable composition suitable for use in providinga controlled sustained release implant is provided, a method for formingthe flowable composition, a method for using the flowable composition,the biodegradable sustained release solid or gel implant that is formedfrom the flowable composition, a method of forming the biodegradableimplant in situ, a method for treating disease through use of thebiodegradable implant and a kit that includes the flowable composition.The flowable composition may preferably be used to provide abiodegradable or bioerodible microporous in situ formed implant inanimals. The flowable composition is composed of a biodegradablethermoplastic polymer in combination with a biocompatible polar aproticorganic liquid and buprenorphine, a metabolite, or a prodrug thereof.The biodegradable thermoplastic polymer is substantially insoluble inaqueous medium and/or in body fluid, biocompatible, and biodegradableand/or bioerodible within the body of a patient. The flowablecomposition may be administered as a liquid or gel into tissue and formsan implant in situ. Alternatively, the implant may be formed ex vivo bycombining the flowable composition with an aqueous medium. In thisembodiment, the preformed implant may be surgically administered to thepatient. In either embodiment, the thermoplastic polymer coagulates orsolidifies to form the solid or gel implant upon the dissipation,dispersement, or leaching of the organic liquid from the flowablecomposition when the flowable composition contacts a body fluid, anaqueous medium, or water. The coagulation or solidification entanglesand entraps the other components of the flowable composition such asbuprenorphine, a metabolite, or a prodrug thereof excipients, organicsubstances, and the like, so that they become dispersed within thegelled or solidified implant matrix. The flowable composition isbiocompatible and the polymer matrix of the implant does not causesubstantial tissue irritation or necrosis at the implant site. Theimplant delivers a sustained level of buprenorphine, a metabolite, or aprodrug thereof to the patient. Preferably, the flowable composition canbe a liquid or a gel, suitable for injection in a patient (e.g., human).

One embodiment surprisingly improves the bioavailability of a sustainedrelease formulation of buprenorphine, a metabolite, or a prodrugthereof. In addition, one embodiment provides: (a) relatively low volumeinjections; (b) improved local tissue tolerance at the injection site;(c) an opportunity to use a subcutaneous injection rather than anintramuscular injection; and (d) less frequent injections compared toother products.

By comparison to formulations derived from other sustained release drugdelivery technologies, the buprenorphine sustained release deliverysystem should provide: (a) superior release kinetics with minimal burst;(b) increased duration of drug release with less frequent injections;(c) markedly improved bioavailability; (d) improved local tissuetolerance due to a small injection volume, and (e) the ability to use ofa subcutaneous injection rather than intramuscular injection. Takentogether, these features make a highly beneficial buprenorphinesustained release delivery system.

Biodegradable Thermoplastic Polymer

The flowable composition is produced by combining a solid, biodegradablethermoplastic polymer, buprenorphine, a metabolite, or a prodrug thereofand a biocompatible polar aprotic organic liquid. The flowablecomposition can be administered by a syringe and needle to a patient inneed of treatment. Any suitable biodegradable thermoplastic polymer canbe employed, provided that the biodegradable thermoplastic polymer is atleast substantially insoluble in body fluid.

The biocompatible, biodegradable, thermoplastic polymer can be made froma variety of monomers which form polymer chains or monomeric unitsjoined together by linking groups. The thermoplastic polymer is composedof a polymer chain or backbone containing monomeric units joined by suchlinking groups as ester, amide, urethane, anhydride, carbonate, urea,esteramide, acetal, ketal, or orthocarbonate groups as well as any otherorganic functional group that can be hydrolyzed by enzymatic orhydrolytic reaction (i.e., is biodegradable by this hydrolytic action).The thermoplastic polymer is typically formed by reaction of startingmonomers containing the reactant groups that should form the backbonelinking groups. For example, alcohols and carboxylic acids should formester linking groups. Isocyanates and amines or alcohols shouldrespectively form urea or urethane linking groups.

Any aliphatic, aromatic, or arylalkyl starting monomer having thespecified functional groups can be used to make the thermoplasticpolymers, provided that the polymers and their degradation products arebiocompatible. The monomer or monomers used in forming the thermoplasticpolymer may be of a single or multiple identity. The resultantthermoplastic polymer should be a homopolymer formed from one monomer,or one set of monomers such as when a diol and diacid are used, or acopolymer, terpolymer, or multi-polymer formed from two or more, orthree or more, or more than three monomers or sets of monomers. Thebiocompatibility specifications of such starting monomers are known inthe art. The thermoplastic polymers are substantially insoluble inaqueous media and body fluids, preferably completely insoluble in suchmedia and fluids. They are also capable of dissolving or dispersing inselected organic liquids having a water solubility ranging fromcompletely soluble in all proportions to water insoluble. Thethermoplastic polymers also are biocompatible.

When used in the flowable composition, the thermoplastic polymer incombination with the organic liquid provides a viscosity of the flowablecomposition that varies from low viscosity, similar to that of water, toa high viscosity, similar to that of a paste, depending on the molecularweight and concentration of the thermoplastic polymer. Typically, thepolymeric composition includes about 5 wt. % to about 95 wt. % of theflowable composition, preferably present in about 15 wt. % to about 70wt. % of the flowable composition or more preferably is present in about25 wt. % to about 50 wt. % of the flowable composition.

In one embodiment, the biodegradable, biocompatible thermoplasticpolymer can be a linear polymer, it can be a branched polymer, or it canbe a combination thereof. Any option is available according to oneembodiment. To provide a branched thermoplastic polymer, some fractionof one of the starting monomers may be at least trifunctional, andpreferably multifunctional. This multifunctional character provides atleast some branching of the resulting polymer chain. For example, whenthe polymer chosen contains ester linking groups along its polymerbackbone, the starting monomers normally should be hydroxycarboxylicacids, cyclic dimers of hydroxycarboxylic acids, cyclic trimers ofhydroxycarboxylic acids, diols, or dicarboxylic acids. Thus, to providea branched thermoplastic polymer, some fraction of a starting monomerthat is at least multifunctional, such as a triol or a tricarboxylicacid is included within the combination of monomers being polymerized toform the thermoplastic polymer. In addition, the polymers mayincorporate more than one multifunctional unit per polymer molecule, andtypically many multifunctional units depending on the stoichiometry ofthe polymerization reaction. The polymers may also optionallyincorporate at least about one multifunctional unit per polymermolecule. A so-called star or branched polymer is formed when about onemultifunctional unit is incorporated in a polymer molecule. Thepreferred thermoplastic polyester may be formed from such monomers ashydroxycarboxylic acids or dimers thereof. Alternatively, athermoplastic polyester may be formed from a dicarboxylic acid and adiol. A branching monomer such as a dihydroxycarboxylic acid would beincluded with the first kind of starting monomer, or a triol and/or atricarboxylic acid would be included with the second kind of startingmonomer if a branched polyester were desired. Similarly, a triol,tetraol, pentaol, or hexaol such as sorbitol or glucose can be includedwith the first kind of starting monomer if a branched or star polyesterwere desired. The same rationale would apply to polyamides. A triamineand/or triacid would be included with starting monomers of a diamine anddicarboxylic acid. An amino dicarboxylic acid, diamino carboxylic acid,or a triamine would be included with the second kind of startingmonomer, amino acid. Any aliphatic, aromatic, or arylalkyl startingmonomer having the specified functional groups can be used to make thebranched thermoplastic polymers, provided that the polymers and theirdegradation products are biocompatible. The biocompatibilityspecifications of such starting monomers are known in the art.

The monomers used to make the biocompatible thermoplastic polymersshould produce polymers or copolymers that are thermoplastic,biocompatible, and biodegradable. Suitable thermoplastic, biocompatible,biodegradable polymers suitable for use as the biocompatiblethermoplastic branched polymers include, for example, polyesters,polylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals,polyketals, polycarbonates, polyorthocarbonates, polyorthoesters,polyphosphoesters, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), poly(amino acids), and copolymers, terpolymers,combinations, or mixtures of the above materials. Suitable examples ofsuch biocompatible, biodegradable, thermoplastic polymers are disclosed,e.g., in U.S. Pat. Nos. 4,938,763, 5,278,201, 5,324,519, 5,702,716,5,744,153, 5,990,194, 6,461,631, and 6,565,874.

The polymer composition can also include, for example, polymer blends ofthe polymers with other biocompatible polymers, so long as they do notinterfere undesirably with the biodegradable characteristics of thecomposition. Blends of the polymer with such other polymers may offereven greater flexibility in designing the precise release profiledesired for targeted drug delivery or the precise rate ofbiodegradability desired for implants.

The preferred biocompatible thermoplastic polymers or copolymers arethose which have a lower degree of crystallization and are morehydrophobic. These polymers and copolymers are more soluble in thebiocompatible organic liquids than highly crystalline polymers such aspolyglycolide, which has a high degree of hydrogen-bonding. Preferredmaterials with the desired solubility parameters are polylactides,polycaprolactones, and copolymers of these with glycolide so as toprovide more amorphous regions to enhance solubility. Generally, thebiocompatible, biodegradable thermoplastic polymer is substantiallysoluble in the organic liquid so that solutions, dispersions, ormixtures up to about 50-60 wt. % solids can be made. Preferably, thepolymers are typically completely soluble in the organic liquid so thatsolutions, dispersions, or mixtures up to about 85-98 wt. % solids canbe made. The polymers also are at least substantially insoluble in waterso that less than about 0.1 g of polymer per mL of water should dissolveor disperse in water. Preferably, the polymers are typically completelyinsoluble in water so that less than about 0.001 g of polymer per mL ofwater should dissolve or disperse in water. At this preferred level, theflowable composition with a completely water miscible organic liquidshould almost immediately transform to the solid implant.

Optionally, the delivery system may also contain a combination of anon-polymeric material and an amount of a thermoplastic polymer. Thecombination of non-polymeric material and thermoplastic polymer may beadjusted and designed to provide a more coherent buprenorphine sustainedrelease delivery system. Non-polymeric materials useful are those thatare biocompatible, substantially insoluble in water and body fluids, andbiodegradable and/or bioerodible within the body of an animal. Thenon-polymeric material is capable of being at least partiallysolubilized in an organic liquid. In the flowable composition containingsome organic liquid or other additive, the non-polymeric materials arealso capable of coagulating or solidifying to form a solid or gelimplant upon the dissipation, dispersement or leaching of the organicliquid component from the flowable composition upon contact of theflowable composition with a body fluid. The matrix of all embodiments ofthe implant including a non-polymeric material should have a consistencyranging from gelatinous to impressionable and moldable, to a hard, densesolid.

Non-polymeric materials that can be used in the delivery systemgenerally include, for example, any having the foregoingcharacteristics. Suitable useful non-polymeric materials include, forexample, sterols such as cholesterol, stigmasterol, beta-sistosterol,and estradiol; cholesteryl esters such as cholesteryl stearate, C18-C36mono-, di-, and tricylglycerides such as glyceryl monooleate, glycerylmonolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glycerylmonomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryldidocosanoate, glyceryl dimyristate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glyceryl tristearate, and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate, and sorbitan tristearate; C16-C18fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof spingomyelins such as stearyl, palmitoyl, andtricosanyl sphingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; andcombinations and mixtures thereof. Preferred non-polymeric materialsinclude, for example, cholesterol, glyceryl monostearate, glyceryltristearate, stearic acid, stearic anhydride, glyceryl monooleate,glyceryl monolinoleate, and acetylated monoglycerides. The polymeric andnon-polymeric materials may be selected and/or combined to control therate of biodegradation, bioerosion, and/or bioabsorption within theimplant site. Generally, the implant matrix should breakdown over aperiod from about 1 week to about 12 months, preferably over a period ofabout 1 week to about 4 months.

Thermoplastic Polymer Molecular Weight

The molecular weight of the polymer can affect the rate ofbuprenorphine, a metabolite, or a prodrug thereof release from theimplant. Under these conditions, as the molecular weight of the polymerincreases, the rate of buprenorphine, a metabolite, or a prodrug thereofrelease from the system decreases. This phenomenon can be advantageouslyused in the formulation of systems for the controlled release ofbuprenorphine, a metabolite, or a prodrug thereof. For faster release ofbuprenorphine, a metabolite, or a prodrug thereof, low molecular weightpolymers can be chosen to provide the desired release rate. For releaseof buprenorphine, a metabolite, or a prodrug thereof over a relativelylong period of time, a higher polymer molecular weight can be chosen.Accordingly, a buprenorphine sustained release delivery system can beproduced with an optimum polymer molecular weight range for the releaseof buprenorphine, a metabolite, or a prodrug thereof over a selectedlength of time. The molecular weight of a polymer can be varied by anyof a variety of methods. The choice of method is typically determined bythe type of polymer composition. For example, if a thermoplasticpolyester is used that is biodegradable by hydrolysis, the molecularweight can be varied by controlled hydrolysis, such as in a steamautoclave. Typically, the degree of polymerization can be controlled,for example, by varying the number and type of reactive groups and thereaction times.

The control of molecular weight and/or inherent viscosity of thethermoplastic polymer is a factor involved in the formation andperformance of the implant. In general, thermoplastic polymers withhigher molecular weight and higher inherent viscosity should provide animplant with a slower degradation rate and therefore a longer duration.Changes and fluxuations of the molecular weight of the thermoplasticpolymer following the compounding of the delivery system should resultin the formation of an implant that shows a degradation rate andduration substantially different from the degradation rate and durationdesired or predicted.

The useful thermoplastic polymers may have average molecular weightsranging from about 1 kiloDalton (kDa) to about 100 kDa. Preferably, thebiodegradable thermoplastic polymer has an average molecular weight ofabout 5,000 Daltons (Da) to about 40,000 Daltons, or more preferablyabout 10,000 Daltons to about 20,000 Daltons.

The molecular weight may also be indicated by the inherent viscosity(abbreviated as “IV.”, units are in deciliters/gram). Generally, theinherent viscosity of the thermoplastic polymer is a measure of itsmolecular weight and degradation time (e.g., a thermoplastic polymerwith a high inherent viscosity has a higher molecular weight and longerdegradation time). Preferably, the thermoplastic polymer has a molecularweight, as shown by the inherent viscosity, from about 0.05 dL/g toabout 0.5 dL/g (as measured in chloroform), more preferably from about0.10 dL/g to about 0.30 dL/g.

Characteristics of Preferred Polyester

The preferred thermoplastic biodegradable polymer of the flowablecomposition is a polyester. Generally, the polyester may be composed ofunits of about one or more hydroxycarboxylic acid residues wherein thedistribution of differing units may be random, block, paired, orsequential. Alternatively, the polyester may be composed of units ofabout one or more diols and about one or more dicarboxylic acids. Thedistribution should depend upon the starting materials used tosynthesize the polyester and upon the process for synthesis. An exampleof a polyester composed of differing paired units distributed in blockor sequential fashion is a poly(lactide-co-glycolide). An example of apolyester composed of differing unpaired units distributed in randomfashion is poly(lactic acid-co-glycolic acid). Suitable biodegradablethermoplastic polyesters include, for example, polylactides,polyglycolides, polycaprolactones, copolymers thereof, terpolymersthereof, and any combinations thereof. Preferably, the suitablebiodegradable thermoplastic polyester is a polylactide, a polyglycolide,a copolymer thereof, a terpolymer thereof, or a combination thereof.

The terminal groups of the poly(DL-lactide-co-glycolide) can either behydroxyl, carboxyl, or ester depending upon the method ofpolymerization. Polycondensation of lactic or glycolic acid shouldprovide a polymer with terminal hydroxyl and carboxyl groups.Ring-opening polymerization of the cyclic lactide or glycolide monomerswith water, lactic acid, or glycolic acid should provide polymers withthese same terminal groups. However, ring-opening of the cyclic monomerswith a mono functional alcohol such as methanol, ethanol, or 1-dodecanolshould provide a polymer with about one hydroxyl group and about oneester terminal group. Ring-opening polymerization of the cyclic monomerswith a polyol such as glucose, 1,6-hexanediol, or polyethylene glycolshould provide a polymer with hydroxyl terminal groups. Such apolymerization of dimers of hydroxylcarboxylic acids and a polyol is achain extension of the polymer. The polyol acts as a centralcondensation point with the polymer chain growing from the hydroxylgroups incorporated as ester moieties of the polymer. The polyol may bea diol, triol, tetraol, pentaol, or hexaol of about 2 to about 30carbons in length. Examples include saccharides, reduced saccharidessuch as sorbitol, diols such as hexane-1,6-diol, triols such as glycerolor reduced fatty acids, and similar polyols. Generally, the polyesterscopolymerized with alcohols or polyols should provide longer durationimplants.

The type, molecular weight, and amount of the preferred biodegradablethermoplastic polyester present in the flowable composition shouldtypically depend upon the desired properties of the controlled sustainedrelease implant. For example, the type, molecular weight, and amount ofbiodegradable thermoplastic polyester can influence the length of timein which the buprenorphine, a metabolite, or a prodrug thereof isreleased from the controlled sustained release implant. Specifically, inone embodiment, the composition can be used to formulate a one monthsustained release delivery system of buprenorphine, a metabolite, or aprodrug thereof. In such an embodiment, the biodegradable thermoplasticpolyester can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5poly(DL-lactide-co-glycolide) having a carboxy terminal group,preferably a 50/50 poly(DL-lactide-co-glycolide) having a carboxyterminal group; can be present in about 20 wt. % to about 70 wt. % ofthe composition; and can have an average molecular weight of about 5,000Daltons to about 40,000 Daltons, or preferably about 10,000 Daltons toabout 20,000 Daltons.

In one embodiment, the flowable composition can be formulated to providea sustained release delivery system of buprenorphine, a metabolite, or aprodrug thereof. In such an embodiment, the biodegradable thermoplasticpolyester can be a 50/50, 55/45, 75/25, poly(DL-lactide-co-glycolide)with a carboxy terminal group; preferably be a 50/50poly(DL-lactide-co-glycolide) with a carboxy terminal group; can bepresent in about 20 wt. % to about 50 wt. % of the composition; and canhave an average molecular weight of about 5,000 Daltons to about 40,000Daltons, or preferably about 10,000 Daltons to about 20,000 Daltons.

Polar Aprotic Organic Solvent

Organic liquids suitable for use in the flowable composition arebiocompatible and display a range of solubilities in aqueous medium,body fluid, or water. That range includes complete insolubility at allconcentrations upon initial contact, to complete solubility at allconcentrations upon initial contact between the organic liquid and theaqueous medium, body fluid, or water.

While the solubility or insolubility of the organic liquid in water canbe used as a solubility guide, its water solubility or insolubility inbody fluid typically should vary from its solubility or insolubility inwater. Relative to water, body fluid contains physiologic salts, lipids,proteins, and the like, and should have a differing solvating abilityfor organic liquids. This phenomenon is similar to the classic “saltingout” characteristic displayed by saline relative to water. Body fluiddisplays similar variability relative to water but in contrast to a“salting out” factor, body fluid typically has a higher solvatingability for most organic liquids than water. This higher ability is duein part to the greater lipophilic character of body fluid relative towater, and also in part to the dynamic character of body fluid. In aliving organism, body fluid is not static but rather moves throughoutthe organism. In addition, body fluid is purged or cleansed by tissuesof the organism so that body fluid contents are removed. As a result,body fluid in living tissue should remove, solvate, or dissipate organicliquids that are utterly insoluble in water.

Pursuant to the foregoing understanding of the solubility differencesamong water, aqueous media, and body fluid, the organic liquid may becompletely insoluble to completely soluble in water when the two areinitially combined. Preferably the organic liquid is at least slightlysoluble, more preferably moderately soluble, especially more preferablyhighly soluble, and most preferably soluble at all concentrations inwater. The corresponding solubilities of the organic liquids in aqueousmedia and body fluid should tend to track the trends indicated by thewater solubilities. In body fluid, the solubilities of the organicliquids should tend to be higher than those in water. When an organicliquid that is insoluble to slightly soluble in body fluid is used inany of the embodiments of the sustained release delivery system, itshould allow water to permeate into the implanted delivery system over aperiod of time ranging from seconds to weeks or months. This process maydecrease or increase the delivery rate of the buprenorphine, ametabolite, or a prodrug thereof and in the case of the flowablecomposition, it should affect the rate of coagulation or solidification.When an organic liquid that is moderately soluble to very soluble inbody fluid is used in any of the embodiments of the delivery system, itshould diffuse into body fluid over a period of minutes to days. Thediffusion rate may decrease or increase the delivery rate of thebuprenorphine, a metabolite, or a prodrug thereof. When highly solubleorganic liquids are used, they should diffuse from the delivery systemover a period of seconds to hours. Under some circumstances, this rapiddiffusion is responsible at least in part for the so-called bursteffect. The burst effect is a short-lived but rapid release ofbuprenorphine, a metabolite, or a prodrug thereof upon implantation ofthe delivery system followed by a long-lived, slow release ofbuprenorphine, a metabolite, or a prodrug thereof.

Organic liquids used in the delivery system include, for example,aliphatic, aryl, and arylalkyl; linear, cyclic, and branched organiccompounds that are liquid or at least flowable at ambient andphysiological temperature and contain such functional groups asalcohols, alkoxylated alcohols, ketones, ethers, polymeric ethers,amides, esters, carbonates, sulfoxides, sulfones, any other functionalgroup that is compatible with living tissue, and any combinationthereof. The organic liquid preferably is a polar aprotic, or polarprotic organic solvent. Preferably, the organic liquid has a molecularweight in the range of about 30 to about 1000.

Preferred biocompatible organic liquids that are at least slightlysoluble in aqueous or body fluid include, for example,N-methyl-2-pyrrolidone, 2-pyrrolidone; (C1-C15) alcohols, diols, triols,and tetraols such as ethanol, glycerin, propylene glycol, and butanol;(C3-C15) esters and alkyl esters of mono-, di-, and tricarboxylic acidssuch as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyllactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributylcitrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyladipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,triethyl citrate, acetyl tributyl citrate, and glyceryl triacetate;(C1-C15) amides such as dimethylformamide, dimethylacetamide, andcaprolactam; (C3-C20 ethers such as tetrahydrofuran or solketal; tweens,triacetin, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid,l-dodecylazacycloheptan-2-one, N-methyl-2-pyrrolidone, esters ofcarbonic acid and alkyl alcohols such as propylene carbonate, ethylenecarbonate, and dimethyl carbonate; alcohols such as solketal, glycerolformal, and glycofurol; dialkylamides such as dimethylformamide,dimethylacetamide, dimethylsulfoxide, and dimethylsulfone; lactones suchas epsilon-caprolactone and butyrolactone; cyclic alkyl amides such ascaprolactam; triacetin and diacetin; aromatic amides such asN,N-dimethyl-m-toluamide; and mixtures and combinations thereof.Preferred solvents include, for example, N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate,solketal, triacetin, glycerol formal, isopropylidene glycol, andglycofurol.

Other preferred organic liquids are benzyl alcohol, benzyl benzoate,dipropylene glycol, tributyrin, ethyl oleate, glycerin, glycofural,isopropyl myristate, isopropyl palmitate, oleic acid, polyethyleneglycol, propylene carbonate, and triethyl citrate. The most preferredsolvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide,triacetin, and propylene carbonate because of their solvating abilityand their compatibility.

The type and amount of biocompatible organic liquid present in theflowable composition should typically depend on the desired propertiesof the controlled release implant as described in detail below.Preferably, the flowable composition includes about 10 wt. % to about 90wt. % or more preferably about 30 wt. % to about 70 wt. % of an organicliquid.

The solubility of the biodegradable thermoplastic polymers in thevarious organic liquids should differ depending upon theircrystallinity, their hydrophilicity, hydrogen-bonding, and molecularweight. Lower molecular-weight polymers should normally dissolve morereadily in the organic liquids than high-molecular-weight polymers. As aresult, the concentration of a thermoplastic polymer dissolved in thevarious organic liquids should differ depending upon type of polymer andits molecular weight. Moreover, the higher molecular-weightthermoplastic polymers should tend to give higher solution viscositiesthan the low-molecular-weight materials.

When the organic liquid forms part of the flowable composition, itfunctions to enable easy, non-surgical placement of the sustainedrelease delivery system into living tissue. It also facilitatestransformation of the flowable composition to an in situ formed implant.Although it is not meant as a limitation of the invention, it isbelieved that the transformation of the flowable composition is theresult of the dissipation of the organic liquid from the flowablecomposition into the surrounding body fluid and tissue and the infusionof body fluid from the surrounding tissue into the flowable composition.It is believed that during this transformation, the thermoplasticpolymer and organic liquid within the flowable composition partitioninto regions rich and poor in polymer.

The pliability of the implant can be substantially maintained throughoutits life if additives such as the organic liquid are maintained in theimplant. Such additives also can act as a plasticizer for thethermoplastic polymer and at least in part may remain in the implant.One such additive having these properties is an organic liquid of lowwater solubility to water insolubility. Such an organic liquid providingthese pliability and plasticizing properties may be included in thedelivery system as the sole organic liquid or may be included inaddition to an organic liquid that is moderately to highly watersoluble. Organic liquids of low water solubility or water insolubility,such as those forming aqueous solutions of no more than about 5% byweight in water, can function as a pliability, plasticizing component,and in addition can act as the solvating component for the flowablecomposition embodiment. Such organic liquids can act as plasticizers forthe thermoplastic polymer. When the organic liquid has these properties,it is a member of a subgroup of organic liquids termed “plasticizer.”The plasticizer influences the pliability and moldability of the implantcomposition such that it is rendered more comfortable to the patientwhen implanted. Moreover, the plasticizer has an effect upon the rate ofsustained release of buprenorphine, a metabolite, or a prodrug thereofsuch that the rate can be increased or decreased according to thecharacter of the plasticizer incorporated into the implant composition.In general, the organic liquid acting as a plasticizer is believed tofacilitate molecular movement within the solid or gel thermoplasticmatrix. The plasticizing capability enables polymer molecules of thematrix to move relative to each other so that pliability and easymoldability are provided. The plasticizing capability also enables easymovement of buprenorphine, a metabolite, or a prodrug thereof so that insome situations, the rate of sustained release is either positively ornegatively affected.

High Water Solubility Organic Liquids

A moderate to highly water soluble organic liquid can be generally usedin the flowable composition, especially when pliability should not be anissue after formation of the implant. Use of the highly water solubleorganic liquid should provide an implant having the physicalcharacteristics of an implant made through direct insertion of theflowable composition.

Use of a moderate to highly water soluble organic liquid in flowablecomposition should facilitate intimate combination and mixture of theother components therein. It should promote solid or gel homogeneity andpliability of an ex vivo formed implant so that such an implant can bereadily inserted into appropriate incisions or trocar placements intissue.

Useful, highly water soluble organic liquids include, for example,substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP)and 2-pyrrolidone; (C2-C10)alkanoic acids such as acetic acid and lacticacid, esters of hydroxy acids such as methyl lactate, ethyl lactate,alkyl citrates, and the like; monoesters of polycarboxylic acids such asmonomethyl succinate acid, monomethyl citric acid, and the like; etheralcohols such as glycofurol, glycerol formal, isopropylidene glycol, and2,2-dimethyl-1,3-dioxolone-4-methanol; Solketal; dialkylamides such asdimethylformamide and dimethylacetamide; dimethylsulfoxide (DMSO) anddimethylsulfone; lactones such as epsilon, caprolactone, andbutyrolactone; cyclic alkyl amides such as caprolactam; and mixtures andcombinations thereof. Preferred organic liquids include, for example,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,glycofurol, glycerol formal, and isopropylidene glycol.

Low Water Solubility Organic Liquids/Solvents

As described above, an organic liquid of low or no water solubility(hereinafter low/no liquid) may also be used in the sustained releasedelivery system. Preferably, a low/no liquid is used when it isdesirable to have an implant that remains pliable, is to be extrudableis to have an extended release and the like. For example, the releaserate of the biologically active agent can be affected under somecircumstances through the use of a low/no liquid. Typically suchcircumstances involve retention of the organic liquid within the implantproduct and its function as a plasticizer or rate modifier. Suitable lowor nonsoluble organic liquids include, for example, esters of carbonicacid and aryl alcohols such as benzyl benzoate; (C4-C10)alkyl alcohols;(C1-C6)alkyl(C2-C6) alkanoates; esters of carbonic acid and alkylalcohols such as propylene carbonate, ethylene carbonate, and dimethylcarbonate, alkyl esters of mono-, di-, and tricarboxylic acids, such as2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl butyrate,diethyl malonate, diethyl glutonate, tributyl citrate, diethylsuccinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethylsuccinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyltributyl citrate, and glyceryl triacetate; alkyl ketones such as methylethyl ketone; as well as other carbonyl, ether, carboxylic ester, amide,and hydroxy containing liquid organic compounds having some solubilityin water. Propylene carbonate, ethyl acetate, triethyl citrate,isopropyl myristate, and glyceryl triacetate are preferred because ofbiocompatibility and pharmaceutical acceptance. Additionally, mixturesof the foregoing high, low, or no solubility organic liquids providingvarying degrees of solubility for the matrix forming material can beused to alter the life time, rate of bioactive agent release, and othercharacteristics of the implant. Examples include a combination ofN-methyl-2-pyrrolidone and propylene carbonate, which provides a morehydrophobic solvent than N-methyl-2-pyrrolidone alone, and a combinationof N-methyl-2-pyrrolidone and polyethylene glycol, which provides a morehydrophilic solvent than N-methyl-2-pyrrolidone alone.

The organic liquid for inclusion in the composition should bebiocompatible. Biocompatible means that as the organic liquid dispersesor diffuses from the composition, it does not result in substantialtissue irritation or necrosis surrounding the implant site.

Organic Liquid for the Preferred Flowable Composition

For the preferred flowable composition incorporating a thermoplasticpolyester, any suitable polar aprotic organic liquid can be employed,provided that the suitable polar aprotic solvent displays a body fluidsolubility within a range of completely soluble in all proportions tovery slightly soluble. Suitable polar aprotic organic liquids aredisclosed, e.g., in ALDRICH HANDBOOK OF FINE CHEMICALS AND LABORATORYEQUIPMENT, Milwaukee, Wis. (2000) and in U.S. Pat. Nos. 5,324,519,4,938,763, 5,702,716, 5,744,153, and 5,990,194. A suitable polar aproticliquid should be able to diffuse over time into body fluid so that theflowable composition coagulates or solidifies. The diffusion may berapid or slow. It is also preferred that the polar aprotic liquid forthe biodegradable polymer be non-toxic and otherwise biocompatible.

The polar aprotic organic liquid is preferably biocompatible. Suitablepolar aprotic organic liquid include, for example, those having an amidegroup, an ester group, a carbonate group, a ketone, an ether, a sulfonylgroup, or a combination thereof. Preferably, the polar aprotic organicliquid comprises N-methyl-2-pyrrolidone, 2-pyrrolidone,N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate,caprolactam, triacetin, or any combination thereof. More preferably, thepolar aprotic organic solvent is N-methyl-2-pyrrolidone.

The solubility of the biodegradable thermoplastic polyesters in thevarious polar aprotic liquids should differ depending upon theircrystallinity, their hydrophilicity, hydrogen-bonding, and molecularweight. Thus, not all of the biodegradable thermoplastic polyestersshould be soluble to the same extent in the same polar aprotic organicliquid, but each biodegradable thermoplastic polymer or copolymer shouldbe soluble in its appropriate polar aprotic solvent. Lowermolecular-weight polymers should normally dissolve more readily in theliquids than high-molecular-weight polymers. As a result, theconcentration of a polymer dissolved in the various liquids shoulddiffer depending upon type of polymer and its molecular weight.Conversely, the higher molecular-weight polymers should normally tend tocoagulate or solidify faster than the very low-molecular-weightpolymers. Moreover the higher molecular-weight polymers should tend togive higher solution viscosities than the low-molecular-weightmaterials.

For example, low-molecular-weight polylactic acid formed by thecondensation of lactic acid should dissolve in N-methyl-2-pyrrolidone(NMP) to give about 73% by weight solution which still flows easilythrough a 23-gauge syringe needle, whereas a higher molecular-weightpoly(DL-lactide) (DL-PLA) formed by the additional polymerization ofDL-lactide gives the same solution viscosity when dissolved inN-methyl-2-pyrrolidone at about 50% by weight. The highermolecular-weight polymer solution coagulates immediately when placedinto water. The low-molecular-weight polymer solution, although moreconcentrated, tends to coagulate very slowly when placed into water.

It has also been found that solutions containing very highconcentrations of high molecular weight polymers sometimes coagulate orsolidify slower than more dilute solutions. It is believed that the highconcentration of polymer impedes the diffusion of solvent from withinthe polymer matrix and consequently prevents the permeation of waterinto the matrix where it can precipitate the polymer chains. Thus, thereis an optimum concentration at which the solvent can diffuse out of thepolymer solution and water penetrates within to coagulate the polymer.

The concentration and species of the polar aprotic organic liquid forthe preferred flowable composition incorporating a thermoplasticpolyester should typically depend upon the desired properties of thecontrolled release implant. For example, the species and amount ofbiocompatible polar aprotic solvent can influence the length of time inwhich the buprenorphine, a metabolite, or a prodrug thereof is releasedfrom the controlled release implant.

Specifically, in one embodiment, the flowable composition can be used toformulate a one month delivery system of buprenorphine, a metabolite, ora prodrug thereof. In such an embodiment, the biocompatible polaraprotic solvent can preferably be N-methyl-2-pyrrolidone and canpreferably present in about 30 wt. % to about 70 wt. % of thecomposition.

Alternatively, in another embodiment, the composition can be used toformulate a three month delivery system of buprenorphine, a metabolite,or a prodrug thereof. In such an embodiment, the biocompatible polaraprotic solvent can preferably be N-methyl-2-pyrrolidone and canpreferably present in about 30 wt. % to about 70 wt. % of thecomposition.

Buprenorphine

Buprenorphine (also known as(2S)-2-[(−)-(5R,6R,7R,14S)-9α-cyclo-propyl-methyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-di-methylbutan-2-oland marketed under the trade names SUBUTEX® and SUBOXONE® by Indivior UKLimited) is an opioid agonist agent belonging to the chemical class ofthebaine derivatives. Buprenorphine, a metabolite, or a prodrug thereofmay be administered in its unneutralized basic form, or as a salt of anorganic or inorganic acid. Examples include the buprenorphine, ametabolite, or a prodrug thereof salts wherein the gegenion(counter-ion) is acetate, propionate, tartrate, malonate, chloride,sulfate, bromide, and other pharmaceutically acceptable organic andinorganic acid gegenions.

Buprenorphine, a metabolite, or a prodrug thereof may be lyophilizedprior to use. Typically, the buprenorphine, a metabolite, or a prodrugthereof may be dissolved in an aqueous solution, sterile filtered, andlyophilized in a syringe. In a separate process, the thermoplasticpolymer/organic liquid solution can be filled into second syringe. Thetwo syringes can be coupled together and the contents can be drawn backand forth between the two syringes until the thermoplastic polymer,organic liquid, and the buprenorphine, a metabolite, or a prodrugthereof are effectively mixed together, forming a flowable composition.The flowable composition can be drawn into one syringe. The two syringescan be disconnected and a needle attached to the syringe containing theflowable composition. The flowable composition can be injected throughthe needle into the body. The flowable composition can be formulated andadministered to a patient as described in, e.g., U.S. Pat. Nos.5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194; or asdescribed herein. Once administered, the organic liquid dissipates, theremaining polymer gels or solidifies, and a matrix structure is formed.The organic liquid should dissipate and the polymer should solidify orgel so as to entrap or encase the buprenorphine, a metabolite, or aprodrug thereof within the matrix.

The release of buprenorphine, a metabolite, or a prodrug thereof fromthe implant should follow the same general rules for release of a drugfrom a monolithic polymeric device. The release of buprenorphine, ametabolite, or a prodrug thereof can be affected by the size and shapeof the implant, the loading of buprenorphine, a metabolite, or a prodrugthereof within the implant, the permeability factors involving thebuprenorphine, a metabolite, or a prodrug thereof and the particularpolymer, and the degradation of the polymer. Depending upon the amountof buprenorphine, a metabolite, or a prodrug thereof selected fordelivery, the above parameters can be adjusted by one skilled in the artof drug delivery to give the desired rate and duration of release.

The amount of buprenorphine, a metabolite, or a prodrug thereofincorporated into the sustained release delivery system depends upon thedesired release profile, the concentration of buprenorphine, ametabolite, or a prodrug thereof used for a biological effect, and thelength of time that the buprenorphine, a metabolite, or a prodrugthereof has to be released for treatment. There is no upper limit on theamount of buprenorphine, a metabolite, or a prodrug thereof incorporatedinto the sustained release delivery system except for that of anacceptable solution or dispersion viscosity for injection through asyringe needle. The lower limit of buprenorphine, a metabolite, or aprodrug thereof incorporated into the sustained release delivery systemis dependent upon the activity of the buprenorphine, a metabolite, or aprodrug thereof and the length of time needed for treatment.Specifically, in one embodiment, the sustained release delivery systemcan be formulated to provide a one month release of buprenorphine, ametabolite, or a prodrug thereof. In such an embodiment, thebuprenorphine, a metabolite, or a prodrug thereof can preferably bepresent in about 0.5 wt. % to about 50 wt. %, preferably about 1 wt. %to about 30 wt. % of the composition. Alternatively, in anotherembodiment, the sustained release delivery system can be formulated toprovide a three month delivery of buprenorphine, a metabolite, or aprodrug thereof. In such an embodiment, the buprenorphine, a metabolite,or a prodrug thereof can preferably be present in about 0.5 wt. % toabout 50 wt. %, preferably about 1 wt. % to about 30 wt. % of thecomposition. The gel or solid implant formed from the flowablecomposition should release the buprenorphine, a metabolite, or a prodrugthereof contained within its matrix at a controlled rate until theimplant is effectively depleted of buprenorphine, a metabolite, or aprodrug thereof.

Adjuvants and Carriers

The sustained release delivery system may include, for example, arelease rate modifier to alter the sustained release rate ofbuprenorphine, a metabolite, or a prodrug thereof from the implantmatrix. The use of a release rate modifier may either decrease orincrease the release of buprenorphine, a metabolite, or a prodrugthereof in the range of several times of differences as compared to therelease of buprenorphine, a metabolite, or a prodrug thereof from animplant matrix without the release rate modifier.

With the addition of a hydrophobic release rate modifier such ashydrophobic ethyl heptanoate, to the sustained release delivery system,and formation of the implant matrix through interaction of the flowablecomposition and body fluid, the release rate of buprenorphine, ametabolite, or a prodrug thereof can be slowed. Hydrophilic release ratemodifiers such as polyethylene glycol may increase the release of thebuprenorphine, a metabolite, or a prodrug thereof. By an appropriatechoice of the polymer molecular weight in combination with an effectiveamount of the release rate modifier, the release rate and extent ofrelease of a buprenorphine, a metabolite, or a prodrug thereof from theimplant matrix may be varied, for example, from relatively fast torelatively slow.

Useful release rate modifiers include, for example, organic substanceswhich are water-soluble, water-miscible, or water insoluble (i.e.,hydrophilic to hydrophobic).

The release rate modifier is preferably an organic compound which isthought to increase the flexibility and ability of the polymer moleculesand other molecules to slide past each other even though the moleculesare in the solid or highly viscous state. It is preferred that a releaserate modifier is compatible with the combination of polymer and organicliquid used to formulate the sustained release delivery system. It isfurther preferred that the release rate modifier is apharmaceutically-acceptable substance.

Useful release rate modifiers include, for example, fatty acids,triglycerides, other like hydrophobic compounds, organic liquids,plasticizing compounds, and hydrophilic compounds. Suitable release ratemodifiers include, for example, esters of mono-, di-, and tricarboxylicacids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate,diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyladipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate,glycerol triacetate, di(n-butyl) sebecate, and the like; polyhydroxyalcohols, such as propylene glycol, polyethylene glycol, glycerin,sorbitol, and the like; fatty acids; triesters of glycerol, such astriglycerides, epoxidized soybean oil, and other epoxidized vegetableoils; sterols, such as cholesterol; alcohols, such as (C6-C12) alkanols,2-ethoxyethanol, and the like. The release rate modifier may be usedsingly or in combination with other such agents. Suitable combinationsof release rate modifiers include, for example, glycerin/propyleneglycol, sorbitol/glycerin, ethylene oxide/propylene oxide, butyleneglycol/adipic acid, and the like. Preferred release rate modifiersinclude, for example, dimethyl citrate, triethyl citrate, ethylheptanoate, glycerin, and hexanediol.

The amount of the release rate modifier included in the flowablecomposition should vary according to the desired rate of release of thebuprenorphine, a metabolite, or a prodrug thereof from the implantmatrix. Preferably, the sustained release delivery system contains about0.5 to about 30%, preferably about 5 to about 10%, of a release ratemodifier.

Other solid adjuvants may also be optionally combined with the sustainedrelease delivery system to act as carriers, especially isolationcarriers. These include, for example, additives or excipients such as astarch, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, and/orpolyvinylpyrrolidone.

Additional adjuvants may include, for example, oils such as peanut oil,sesame oil, cottonseed oil, corn oil, and olive oil as well as esters offatty acids such as ethyl oleate, isopropyl myristate, fatty acidglycerides, and acetylated fatty acid glycerides. Also included arealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol); petroleum hydrocarbons such asmineral oil and petrolatum may also be used in the formulations.Pectins, carbomers, methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, or carboxymethyl cellulose may also beincluded. These compounds can serve as isolation carriers by coating thebuprenorphine, a metabolite, or a prodrug thereof thereby preventing itscontact with the organic solvent and other ingredients of the flowablecomposition. As isolation carriers, these compounds also help lower theburst effect associated with the coagulation of the flowable compositionin situ.

Optionally, other compounds such as, but not limited to, stabilizers,antimicrobial agents, antioxidants, pH modifiers, bioavailabilitymodifiers, and combinations of these are included. Emulsifiers andsurfactants such as fatty acids or a non-ionic surfactants includingnatural or synthetic polar oil, fatty acid esters, polyol ethers, andmono-, di-, or tri-glycerides may also be included.

The Implant

When the implant is formed, the implant has the physical state of asolid. The solid embodiments may be rigid so that they cannot be flexedor bent by squeezing them between the fingers or they may be flexible orbendable so that they can be compressed or flexed out of original shapeby squeezing between the fingers (i.e., a low amount of force). Thethermoplastic polymer functions as a matrix in these embodiments toprovide integrity to the single body solid and to enable controlledrelease of the bioactive agent upon implantation.

The thermoplastic polymer matrix is preferably a solid matrix andespecially preferably is microporous. In an embodiment of themicroporous solid matrix, there is a core surrounded by a skin. The corepreferably contains pores of diameters from about 1 to about 1000microns. The skin preferably contains pores of smaller diameters thanthose of the core pores. In addition, the skin pores are preferably of asize such that the skin is functionally non-porous in comparison withthe core.

Because all of the components of the implant are biodegradable or can beswept away from the implant site by body fluid and eliminated from thebody, the implant eventually disappears. The implant components maycomplete their biodegradation or disappearance before, after or at thesame time as the buprenorphine, a metabolite, or a prodrug thereof hasbeen typically completely released. The structure of the thermoplasticpolymer, its molecular weight, the density and porosity of the implant,and the body location of the implant all affect the biodegradation anddisappearance rates. The implant is typically formed subcutaneously in apatient. It can be molded in place upon injection to provide comfort tothe patient. The implant volume typically may be between about 0.25 mLto about 3 mL in size.

Therapeutic Use

Surprisingly, it has been discovered that the sustained release deliverysystem is highly effective in delivering buprenorphine. Specifically, asshown in the Examples below, the blood levels of buprenorphine obtainedwith the sustained release delivery system are from about 0.5 nanogramsper milliliter (ng/mL) to about 20 ng/mL in dogs after a 60 mgbuprenorphine dose injection in beagles.

In general, any disease which may be ameliorated, treated, cured, orprevented by administration of buprenorphine, a metabolite, or a prodrugthereof or a buprenorphine analog may be treated by administration ofthe flowable composition. These diseases relate to mental impairments.The following specific malconditions are exemplary of such diseases.These may all be treated by appropriate, effective administration of aflowable composition formulated to deliver an effective amount ofbuprenorphine, a metabolite, or a prodrug thereof. These malconditionsinclude: addiction to opioid substances and chronic pain, and the like.

Dosages

The amount of flowable composition administered should typically dependupon the desired properties of the controlled release implant. Forexample, the amount of flowable composition can influence the length oftime in which the buprenorphine, a metabolite, or a prodrug thereof isreleased from the controlled release implant. Specifically, in oneembodiment, the composition can be used to formulate a one monthdelivery system of buprenorphine, a metabolite, or a prodrug thereof, hisuch an embodiment, about 0.20 mL to about 2.0 mL of the flowablecomposition can be administered. Alternatively, in another embodiment,the composition can be used to formulate a three month delivery systemof buprenorphine, a metabolite, or a prodrug thereof. In such anembodiment, about 0.5 mL to about 2.0 mL of the flowable composition canbe administered. The amount of buprenorphine, a metabolite, or a prodrugthereof within the flowable composition and the resulting implant shoulddepend upon the disease to be treated, the length of duration desired,and the bioavailability profile of the implant. Generally, the effectiveamount should be within the discretion and wisdom of the patient'sattending physician. Guidelines for administration include, for example,dose ranges of from about 1 to about 16 milligrams (mg) ofbuprenorphine, a metabolite, or a prodrug thereof per day, preferablyfrom about 1 to about 5 milligrams (mg) of buprenorphine, a metabolite,or a prodrug thereof per day, as applied for The typical flowablecomposition effective for such sustained delivery over a 1 month periodshould contain from about 3 to about 300 mg of buprenorphine, ametabolite, or a prodrug thereof per ml of total volume of flowablecomposition. The injection volume should range from about 0.2 to about2.0 mL per implant. The typical flowable composition effective for suchsustained delivery of a 3 month period should contain from about 9 toabout 900 mg of buprenorphine, a metabolite, or a prodrug thereof per mlof total volume of flowable composition. The injection volume shouldrange from 0.5 to about 2.0 mL per implant. The polymer formulationshould be the primary factor for obtaining the longer sustained release,as discussed above.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention should now be illustrated with the following non-limitingexamples. The following Examples employ the ATRIGEL® formulation ofpoly(lactide-co-glycolide) and N-methyl-2-pyrrolidone in combinationwith buprenorphine as the flowable composition.

EXAMPLES

In the following Examples, ATRIGEL®/Buprenorphine refers toATRIGEL®/Buprenorphine formulations; ATRIGEL® is a registered trademarkof Tolmar Therapeutics, Inc., Fort Collins, Colo. The particular form ofATRIGEL® product used in these examples is provided with the examples.Unless otherwise indicated, the ATRIGEL® product is the thermoplasticpolymer poly(lactide-co-glycolide) (PLG), the thermoplastic polymerpoly(lactide-co-glycolide extended with 1,6-hexane diol) (PLG), or PLGHin the organic solvent N-methyl-2-pyrrolidone. SUBUTEX® and SUBOXONE®are registered trademarks of Indivior UK Limited, Slough, UK.

The ATRIGEL® drug delivery system is a biodegradable polymeric deliverysystem that can be injected as a liquid. Upon injection of theformulation, the polymer solidifies encapsulating the drug. As theprocess of biodegradation begins, the drug is slowly released. Therelease rate of drugs from this type of delivery system can becontrolled by the type and molecular weight of the polymer and drug loadof the constituted product. Therefore, the system can be tailored tomeet the needs of the patient.

The ATRIGEL® Delivery System is currently used in the Food and DrugAdministration approved products ELIGARD® (one, three, and four-monthsubcutaneous depot formulations of leuprolide acetate) and ATRIDOX®(doxycycline hyclate applied to the periodontal pocket). Clinicalstudies and post-marketing experience with these products demonstratethat the ATRIGEL® Delivery System itself is well tolerated and providesconsistent, sustained release of the incorporated drug over thedesignated dosing period.

These features represent improvements regardless of the particularapplication, i.e. any buprenorphine responsive disease.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

Test Procedures

Preparation of Polymer Solutions

Polymer stock solutions were prepared by weighing a known amount of eachpolymer solid into individual 20 mL scintillation vials. A known amountof N-methyl-2-pyrrolidone was added to each polymer and the vials wereplaced on a horizontal jar mill. The vials were rotated overnight(possibly over several days) to produce a visually clear polymersolution indicating dissolution of the polymer. Sterilization of thepolymer solution may have been accomplished by gamma irradiation orelectron beam irradiation.

Preparation of Test Article Syringes

The “B” syringes (male syringes) contained buprenorphine powder and wereprepared by weighing drug powder into 3.00 mL Becton Dickinson (BD) malesyringes. The “A” syringes (female syringes) were prepared by weighingATRIGEL® polymer stock solutions into 1.0 mL female syringes.

Preparation of Test Articles (Reconstituted Formulation) for Injection

Immediately prior to injection, “A” and “B” syringes were coupled andmixed by cycling the contents from one syringe to the other for 60cycles. The mixed formulation was finally transferred to the male dosingsyringe for injection. Formulations may also be prepared by dissolvingbuprenorphine in ATRIGEL® polymer stock solutions. In this case,buprenorphine and selected ATRIGEL® were weighed into a scintillationvial, and the vial was shaken and/or heated briefly to completelydissolve buprenorphine. The resulting drug ATRIGEL® solution was thenfilled into dosing syringes for injections.

Reversed Phase High Performance Liquid Chromatography Method for theQuantization of Buprenorphine

The High Performance Liquid Chromatography had the following conditions:Mobile Phase A: 0.065% sodium octanesulfonic acid and 0.1%trifluoroacetic acid in water; Mobile Phase B: 90/10 acetonitrile/0.065%sodium octanesulfonic acid and 0.1% trifluoroacetic acid in water; flowrate: 1.0 ml/min; autosampler temperature: room temperature; columntemperature: 30° C.; detection: 285 run (UV); total run time: 21 min;injection volume: 20 μL; column: Phenomenex Luna C18 250×4.6 mm, 5 μm;column storage: 70/30 acetonitrile/water; each sample run according tothe following gradient program:

Time Mobile Phase A Mobile Phase B 0 100% 0% 2 100% 0% 16  20% 80%  18 0% 100%  20 100% 0% 21 100% 0% approximate retention time ofbuprenorphine: 15.4 minutes.

The standard solution preparation is as follows: standard stock solutionwas made by dissolving approximately 10 mg buprenorphine in 10 mL 1:1formulation dissolution solution [90/5/5 acetonitrile/glacial aceticacid/water]/H2O. A series standards ranging from 40 ppm to 500 ppm wasdiluted with water from the standard stock solution.

Implant Extraction Procedure for Implant Retrieval Study

The freshly retrieved implants were carefully debrided the tissuessurrounding the implants using a surgical blade or scissor. The implantscould be analyzed immediately thereafter or stored in a −20° C. freezeruntil a later time. At the time of analysis, exactly 10 mL of theformulation dissolution solution [90/5/5 acetonitrile/glacial aceticacid/water] was added to the implant vial. The vials were then shaken atabout 200 rpm at room temperature on the orbital shaker for at least 2hours. The vials were then centrifuged at 2500 rpm for 10 minutes. Aftercentrifuge, the vials were carefully removed from the centrifuge. Aportion of the supernatant from the vial was transferred into a HPLCvial and if necessary, the transferred solution in the vial was furtherdiluted using the formulation dissolution solution to a suitableconcentration for HPLC analysis. The vials were then analyzed forbuprenorphine content by the High Performance Liquid Chromatographymethod as described above.

Buprenorphine Analysis in Rat Plasma Samples

This procedure was adopted from Li-Heng Pao et al., Journal ofChromatography B, 746(2000), 241-247. To 1 mL or proper amount of therat plasma sample, 20 μl of internal standard [buprenorphine acidrearrangement product, RX2001M, supplied by RBP], 1 mL 0.5 M sodiumbicarbonate solution, and 3 mL of mixture of n-hexane-isoamyl alcohol(9:1 v/v) were added. The solution was then agitated in a shaker at 200rpm at room temperature for at least 30 minutes. After centrifugationfor 10 minutes at 3000 rpm, the solution was placed in a −86° C. freezerfor 30 minutes. The top organic layer was then transferred to a cleantube and evaporated to dryness under a steam of nitrogen at 65° C. Thesample was reconstituted in 200 μL mobile phase and an aliquot of 50 μLwas injected onto the column.

The High Performance Liquid Chromatography had the following conditions:Mobile Phase: 80/20 acetonitrile/5 mM sodium acetate buffer (pH 3.75);flow rate: 1.2 mL/min; autosampler temperature: room temperature; columntemperature: 25° C.; detection: fluorescence (excitation at 215 nm andemission at 355 nm); total run time: 14 min; injection volume: 50 μL;column: Phenomenex Luna Silica (2) 250×4.6 mm, 5 μm; column storage:100% acetonitrile; approximate retention time for buprenorphine and theinternal standard: 7.9 min and 8.7 min.

Buprenorphine and Norbuprenorphine Analysis in Dog Plasma Samples

Plasma samples from dog studies were analyzed for buprenorphine andnorbuprenorphine levels using a LC-MS-MS method through a contractanalytical service laboratory. The method was developed and validated bythe contracted laboratory. It was a proprietary method that employed aliquid-liquid extraction step followed by LC-MS-MS analysis.

In Vivo Animal Studies

Experimental Procedures: All rat preclinical studies were conducted inmale Sprague-Dawley rats. Five rats per Test Article per time point wereinjected either intramuscularly or subcutaneously under full anesthesiain the dorsal thoracic (DT) region with approximately 100 mg of the TestArticle, described above.

During the course of the study, the animals were observed for overttoxicity and any existing test site abnormalities, including redness,bleeding, swelling, discharge, bruising and Test Article extrusion atthe injection site were observed and recorded. In addition, injectionweights were recorded at administration and body weights were taken andrecorded at administration and at termination. If blood samples weretaken for the study, at selected time points, five rats per Test Articlewere anesthetized and bled (about 5 mL) via cardiac puncture. Blood wascollected in labelled potassium ethylenediaminetetraacetic acid tubes.The blood was centrifuged for 10 min at 3000 rpm. The plasma fractionwas transferred to labelled 5 mL plastic culture tubes and stored at−86° C. The plasma was analyzed using the liquid-liquid extractionmethod described above.

After blood collection or if no blood samples were required for thestudy, the animals were terminated with carbon dioxide and the implantswere retrieved. The implants were debrided excess tissue and were storedat −20° C. until analysis. The retrieved implants were analyzed forbuprenorphine content using the implant analysis method described above.

Pharmacokinetics studies in large animals were performed in male beagledogs. Male beagles with body weights between 8 to 12 kg were selected inthese studies. Six dogs per group were injected subcutaneously in thedorsal thoracic region at a buprenorphine equivalent dose of 60 mg perdog. Exact injection doses were obtained by weighing the injectionsyringe before and after each injection. After injection, the dogs werebled periodically to collect their plasma samples. All plasma sampleswere stored in a −80° C. freezer until analysis. The animals were alsowatched periodically for any sign of toxicity as well as injection sitereactions.

Buprenorphine and norbuprenorphine levels in dog plasma samples weremeasured using a validated LC/MS/MS method through a qualified contractanalytical laboratory as described above.

Example 1 24-Hour Burst Release of Buprenorphine ATRIGEL® in Rats

Eight buprenorphine ATRIGEL® formulations were prepared according to themethods described above. The buprenorphine hydrochloride formulationshad the two-syringe configuration and the buprenorphine free baseformulations were solutions. The eight formulations had the followingcompositions.

Test Articles for Example 1:

1. 10% buprenorphine hydrochloride in 45% 50/50 PLGH (26 kD) and 55%NMP.

2. 10% buprenorphine hydrochloride in 55% 65/35 PLGH (17 kD) and 45%NMP.

3. 10% buprenorphine hydrochloride in 48% 55/45 PLG (22 kD), 2%PEG5000-70/30 PLG (59 kD) and 50% NMP.

4. 10% buprenorphine free base in 45% 50/50 PLGH (26 kD) and 55% NMP.

5. 10% buprenorphine free base in 50% 65/35 PLGH (17 kD) and 50% NMP.

6. 10% buprenorphine free base in 55% 65/35 PLGH (17 kD) and 45% NMP.

7. 10% buprenorphine free base in 50% 55/45 PLG (22 kD) and 50% NMP.

8. 10% buprenorphine free base in 48% 55/45 PLG (22 kD), 2%PEG5000-70/30 PLG (59 kD) and 50% NMP.

Their initial release in 24 hours (initial burst) is shown in Table 1.All formulations had low initial burst less than 10%.

TABLE 1 Buprenorphine 24-hour release (initial burst) after subcutaneousinjection of ATRIGEL ® formulations in rats TA 24-Hour Release %Standard deviation 1 4.6 3.7 2 3.1 2.2 3 2.2 4.0 4 7.5 1.6 5 7.2 0.7 65.5 1.0 7 4.4 4.6 8 8.8 0.7

Example 2 49-Day Buprenorphine Release from Buprenorphine HydrochlorideATRIGEL® in Rats

Three buprenorphine hydrochloride ATRIGEL® formulations were preparedusing the AB two-syringe configuration. They were injectedsubcutaneously in a total of 135 male SD rats. At each time points, fiverats per group were euthanized and the implants were retrieved. The timepoints were 2 hour, 1, 7, 14, 21, 28, 35, 42 and 49 days. Theformulations and the buprenorphine release profiles were shown in Table2 and FIG. 2.

Test Articles for Example 2

1. 20% buprenorphine hydrochloride in 50% 50/50 PLGH (15 kD) and 50%NMP.

2. 20% buprenorphine hydrochloride in 50% 65/35 PLGH (10 kD) and 50%NMP.

3. 20% buprenorphine hydrochloride in 50% 65/35 PLGH (17 kD) and 50%NMP.

TABLE 2 Buprenorphine release after subcutaneous injection ofbuprenorphine hydrochloride ATRIGEL ® formulations in rats Time StandardStandard Standard (Day) TA 1 Deviation TA 2 Deviation TA 3 Deviation0.0833 1.9 1.1 5.5 3.0 −0.6 1.9 1 1.2 3.2 5.8 0.9 −0.2 1.7 7 11.5 4.412.3 1.4 13.2 4.2 14 10.6 7.2 17.8 3.5 15.5 14.3 21 36.1 11.6 37.3 14.214.7 2.0 28 56.0 13.9 66.2 8.3 32.3 6.2 35 72.0 11.9 73.8 13.1 42.8 4.242 81.4 9.0 85.8 2.9 64.1 11.4 49 82.6 15.2 87.6 9.0 63.9 16.5

Example 3 35-Day Buprenorphine Release and Pharmacokinetic Profiles fromBuprenorphine Free Base ATRIGEL® in Rats

Four buprenorphine free base ATRIGEL® formulations were prepared assolutions in ready-to-inject syringes. They were injected subcutaneouslyin a total of 160 male SD rats. At each time points, five rats per groupwere anesthetized and blood samples were taken by cardiac puncture. Therats were then euthanized and the implants were retrieved. Both theretrieved implants and plasma samples were analyzed for buprenorphine asdescribed above. The results are shown in FIG. 3 and FIG. 4.

Test Articles for Examples 3

1. 15% buprenorphine free base in 45% 50/50 PLGH (26 kD) and 55% NMP

2. 20% buprenorphine free base in 40% 50/50 PLGH (17 kD) and 50% NMP

3. 20% buprenorphine free base in 20% 50/50 PLGH (26 kD), 20% 50/50 PLGH(12 kD), and 60% NMP

4. 20% buprenorphine free base in 45% 50/50 PLGH (12 kD) and 55% NMP

TABLE 3 Buprenorphine release after suncutaneous injection ofbuprenorphine free base ATRIGEL ® formulations in rats Time StandardStandard Standard Standard (Day) TA 1 Deviation TA 2 Deviation TA 3Deviation TA 4 Deviation 0.0833 2.6 0.8 1.9 0.7 2.2 0.3 2.6 0.7 3 8.81.7 7.2 1.4 7.3 1.3 6.5 1.2 7 16.5 1.6 13.7 2.0 13.6 2.0 13.0 2.6 1435.8 5.0 28.9 6.9 32.2 7.9 25.1 6.7 17 50.0 14.2 38.2 7.1 29.7 5.4 43.25.3 21 49.1 13.0 45.1 12.1 41.6 9.4 44.3 10.2 28 61.2 8.3 58.2 7.7 62.913.7 59.0 15.5 35 78.7 13.7 64.0 8.6 63.6 15.3 74.7 8.6

TABLE 4 Plasma buprenorphine levels after subcutaneous injection ofbuprenorphine free base ATRIGEL ® formulations in rats Time StandardStandard Standard Standard (Day) TA 1 Deviation TA 2 Deviation TA 3Deviation TA 4 Deviation 0.0833 44.9 17.5 54.4 21.3 64.5 19.6 93.3 27.83 11.4 1.9 10.8 1.7 14.5 3.6 16.9 2.0 7 16.4 2.4 22.4 5.1 21.5 4.7 22.07.7 14 27.9 7.9 22.7 5.1 34.9 11.1 31.0 15.0 17 31.0 4.9 39.7 10.6 30.111.0 44.5 13.8 21 20.0 2.9 28.6 9.0 22.9 3.6 24.3 9.2 28 18.3 5.1 26.64.9 20.3 3.8 20.0 2.9 35 13.6 1.7 17.5 4.7 14.6 6.1 13.7 1.8

Example 4 Pharmacokinetic Study of Two Buprenorphine HydrochlorideATRIGEL® in Dogs

Two buprenorphine hydrochloride ATRIGEL® formulations were preparedusing the AB two-syringe configuration. They were injectedsubcutaneously in a total of 12 male beagle dogs. The dogs were thenbled regularly at each time point to collect their plasma samples. Theplasma samples were analyzed using a validated LC/MS/MS method by acontract analytical service company.

Test Articles for Example 4

TA 1: 20% buprenorphine hydrochloride in 50% 50/50 PLGH (12 kD) and 50%NMP

TA 2: 20% buprenorphine hydrochloride in 50% 50/50 PLGH (21 kD) and 50%NMP

TABLE 5 Mean plasma buprenorphine levels after subcutaneous injection oftwo buprenorphine hydrochloride ATRIGEL ® formulations in Beagles TimePoints TA #1 Time Points TA #2 (Day) (ng/mL) (Day) (ng/mL) Day 0 Hr 112.10 ± 5.42  Day 0 Hr 1 11.80 ± 6.40  Day 0 Hr 2 12.83 ± 3.82  Day 0 Hr2 12.08 ± 3.80  Day 0 Hr 4 7.64 ± 1.57 Day 0 Hr 4 7.26 ± 1.51 Day 0 Hr 84.31 ± 1.20 Day 0 Hr 8 3.85 ± 0.83 1 3.63 ± 1.13 1 2.94 ± 0.76 2 3.42 ±1.54 3 1.29 ± 0.28 3 2.31 ± 0.57 7 1.36 ± 0.52 4 1.88 ± 0.51 10 1.75 ±0.62 7 2.77 ± 1.06 14 2.30 ± 1.24 10 4.15 ± 1.45 17 3.97 ± 2.33 14 7.51± 5.31 20 2.90 ± 1.48 17 7.54 ± 4.88 24 2.45 ± 0.73 21 3.93 ± 3.17 271.98 ± 0.94 24 1.73 ± 1.10 31 1.71 ± 0.94 28 0.90 ± 0.50 38 1.28 ± 0.5231 0.67 ± 0.51 45 0.94 ± 0.24 35 0.58 ± 0.52 52 0.71 ± 0.11 38 0.46 ±0.50 66 0.47 ± 0.19 42 0.26 ± 0.30 80 0.38 ± 0.22 45 0.35 ± 0.42 1220.20 ± 0.07 56 0.26 ± 0.31 63 0.23 ± 0.29 70 0.27 ± 0.36 77 0.29 ± 0.4484 0.33 ± 0.52 91 0.28 ± 0.43 102 0.18 ± 0.29 120 0.22 ± 0.37 147 0.17 ±0.31 183 0.12 ± 0.17

Example 5 Pharmacokinetic Study of Four Buprenorphine Free Base ATRIGEL®in Dogs

Four buprenorphine free base ATRIGEL® formulations were prepared assolutions in ready-to-inject syringes. They were sterilized by eitherirradiation or sterile filtration. They were injected subcutaneously ina total of 24 male beagle dogs. The dogs were then bled regularly ateach time point to collect their plasma samples. The plasma samples wereanalyzed using a validated LC/MS/MS method by a contract analyticalservice company.

Test Articles for Example 5

TA 1: 20% buprenorphine free base in 40% 50/50 PLGH (26 kD) and 60% NMP,irradiated.

TA 2: 20% buprenorphine free base in 40% 50/50 PLGH (12 kD) and 60% NMP,irradiated.

TA 3: 20% buprenorphine free base in 40% 50/50 PLGH (21 kD) and 60% NMP,irradiated.

TA 4: 20% buprenorphine free base in 40% 50/50 PLGH (21 kD) and 60% NMP,filtered.

TABLE 6A Mean plasma buprenorphine levels after subcutaneous injectionof four buprenorphine free base ATRIGEL ® formulations in Beagles TimePoints TA 1 TA 2 (Day) (ng/mL) (ng/mL) Day 0 Hr 1 5.66 ± 2.64 10.25 ±9.75  Day 0 Hr 2 8.00 ± 4.14 14.33 ± 9.96  Day 0 Hr 4 7.00 ± 3.04 11.93± 5.63  Day 0 Hr 8 4.12 ± 1.66 7.00 ± 1.60 1 2.90 ± 1.23 5.99 ± 2.27 21.81 ± 0.68 3.82 ± 0.92 3 1.46 ± 0.62 2.71 ± 0.57 4 1.38 ± 0.52 2.39 ±0.67 7 1.12 ± 0.46 2.37 ± 1.23 10 1.52 ± 0.60 2.65 ± 1.29 14 2.07 ± 1.153.55 ± 2.32 17 2.32 ± 1.24 3.64 ± 2.45 21 2.27 ± 1.11 2.36 ± 1.29 242.53 ± 1.60 2.21 ± 0.85 28 1.95 ± 1.04 1.41 ± 0.60 31 2.12 ± 1.17 1.28 ±0.59 35 1.41 ± 0.52 0.98 ± 0.61 38 1.48 ± 0.76 0.91 ± 0.62 42 1.73 ±0.97 0.90 ± 0.69 45 1.51 ± 0.83 0.89 ± 0.72 49 1.40 ± 0.57 0.68 ± 0.5252 1.35 ± 0.71 0.79 ± 0.65 56 0.89 ± 0.34 0.64 ± 0.50 59 0.80 ± 0.300.59 ± 0.50 63 0.73 ± 0.28 0.56 ± 0.50 66 0.55 ± 0.18 0.59 ± 0.49 700.48 ± 0.17 0.49 ± 0.39 80 0.39 ± 0.19 0.46 ± 0.38 87 0.29 ± 0.20 0.44 ±0.38 94 0.30 ± 0.27 0.46 ± 0.40 115 0.21 ± 0.22 0.22 ± 0.19 129 0.21 ±0.22 0.27 ± 0.24 149 0.22 ± 0.21 0.26 ± 0.21 176 0.10 ± 0.15 0.14 ± 0.13192 0.09 ± 0.14 0.10 ± 0.12

TABLE 6B Mean plasma buprenorphine levels after subcutaneous injectionof four buprenorphine free base ATRIGEL ® formulations in Beagles TimePoints TA 3 TA 4 (Day) (ng/mL) (ng/mL) Day 0 Hr 1 8.30 ± 3.43 6.08 ±5.71 Day 0 Hr 2 10.25 ± 3.22  8.40 ± 6.18 Day 0 Hr 4 8.58 ± 2.99 7.03 ±3.54 Day 0 Hr 8 4.83 ± 1.46 4.32 ± 2.65 1 4.01 ± 1.03 2.58 ± 0.60 3 1.79± 0.33 1.43 ± 0.60 7 1.21 ± 0.35 0.85 ± 0.26 10 1.64 ± 0.60 1.15 ± 0.5714 3.33 ± 1.02 2.23 ± 1.46 17 3.22 ± 0.90 2.07 ± 1.29 20 2.62 ± 0.881.63 ± 1.01 24 2.10 ± 0.71 1.16 ± 0.58 27 2.13 ± 0.80 1.18 ± 0.70 311.93 ± 0.65 1.18 ± 0.64 38 1.60 ± 0.44 1.06 ± 0.58 45 1.37 ± 0.58 1.10 ±0.61 52 0.97 ± 0.63 0.99 ± 0.58 66 0.29 ± 0.23 0.57 ± 0.24 80 0.11 ±0.13 0.26 ± 0.13 94 0.10 ± 0.15 0.20 ± 0.11 108 0.15 ± 0.28 0.20 ± 0.12120 0.12 ± 0.20 0.17 ± 0.11 141 0.08 ± 0.14 0.13 ± 0.11 163 0.14 ± 0.280.12 ± 0.10 183 0.05 ± 0.08 0.12 ± 0.11

Example 6 Drug Release and Pharmacokinetic Studies of an 18%Buprenorphine Free Base ATRIGEL® in Rats and Dogs

A buprenorphine free base ATRIGEL® formulation with 18% buprenorphinewas prepared as a solution in ready-to-inject syringes according to goodmanufacturing practice (GMP) procedures. The formulation was terminallysterilized by gamma irradiation. For the drug release study in rats, theformulation consists of 18% buprenorphine free base, 32% 50/50 PLGH (15kDa), and 50% NMP. The rats were given a dose of 110 mg formulation (20mg buprenorphine) injected subcutaneously. The study was conductedaccording to the procedure described above. Buprenorphine release dataup to 56 days were listed in the following table.

TABLE 7 Buprenorphine release after subcutaneous injection of an 18%buprenorphine free base ATRIGEL ® formulation in rats Time BuprenorphineRelease (Days) (%) 14 24.2 ± 5.9  28 49.9 ± 9.2  42 61.7 ± 13.4 56 80.0± 10.2

A pharmacokinetic study was performed in dogs subsequently. Theformulation was slightly different with a 14 kDa 50/50 PLGH polymer. Agroup of 12 male beagles were selected to be administered 330 mg of theformulation (60 mg buprenorphine) subcutaneously for each animal. Thebeagles were bled regularly at each time point to collect their plasmasamples. Plasma samples were analyzed using a validated LC/MS/MS methodby a contract analytical service company. Buprenorphine plasma levelsduring the course of the study are shown in Table 8 and FIG. 6.

TABLE 8 Mean plasma buprenorphine and norbuprenorphine levels aftersubcutaneous injection of a buprenorphine free base ATRIGEL ® in beaglesTime Buprenorphine level Norbuprenorphine level (Day) (ng/mL) (ng/mL) 00.00 ± 0.00 0.00 ± 0.00 0.042 12.1 ± 5.5   0.859 ± 0.3529 0.083 11.7 ±3.4   0.913 ± 0.1352 0.167 7.18 ± 2.11  0.643 ± 0.1694 0.333 5.10 ± 1.83 0.427 ± 0.1758 1 7.35 ± 4.68  0.234 ± 0.0824 3 2.80 ± 0.99  0.129 ±0.1373 7 2.18 ± 0.94 0.0584 ± 0.0929 10 2.56 ± 1.48 0.0748 ± 0.1223 142.82 ± 1.47 0.0843 ± 0.1298 17 3.26 ± 1.97 0.112 ± 0.142 21 2.91 ± 1.470.0718 ± 0.0669 24 2.49 ± 1.19 0.0694 ± 0.1097 28 1.82 ± 0.82 0.0550 ±0.0804 31 1.65 ± 0.83 0.0874 ± 0.1028 38 0.770 ± 0.426  0.117 ± 0.056545 0.394 ± 0.396 0.0869 ± 0.1138 52 0.301 ± 0.387 0.0158 ± 0.0369 660.214 ± 0.303 0.00 ± 0.00 80 0.170 ± 0.242 0.00 ± 0.00 94 0.107 ± 0.1600.00 ± 0.00 122 0.0444 ± 0.0821 0.00 ± 0.00 150 0.0430 ± 0.0852 0.00 ±0.00 178 0.0218 ± 0.0756 0.00 ± 0.00 206 0.0161 ± 0.0557 0.0532 ± 0.0676

Example 7 Effect of Buprenorphine Drug Loading on Buprenorphine ReleaseProfile

Five buprenorphine free base ATRIGEL® formulations with buprenorphinedrug loadings ranging from 1% to 30% were prepared and filled inready-to-inject syringes according to the method described above. Theformulations with buprenorphine drug loadings of 1% to 20% weresolutions while the 30% buprenorphine formulation was a suspension. Thefive formulations had the following compositions:

Test Articles for Example 7:

1. 1% buprenorphine free base in 40% 50/50 PLGH (21 kDa) and 60% NMP.

2. 5% buprenorphine free base in 40% 50/50 PLGH (21 kDa) and 60% NMP.

3. 10% buprenorphine free base in 40% 50/50 PLGH (21 kDa) and 60% NMP.

4. 20% buprenorphine free base in 40% 50/50 PLGH (21 kDa) and 60% NMP.

5. 30% buprenorphine free base in 45% 50/50 PLGH (26 kDa) and 55% NMP.

Table 9 and FIG. 7 show percentages of buprenorphine released during theentire study time. It shows that initial drug burst was much larger forthe 1% buprenorphine formulation than those of the other formulations.Consequently, its duration of release was shorter than the otherformulations at around 35 days. The data also shows that oncebuprenorphine drug loading was 10% and higher, their release profileswere very comparable. The 1% buprenorphine formulation is less desirablethan those high drug loading formulations due to its large initialburst.

TABLE 9 Buprenorphine release after subcutaneous injection ofbuprenorphine free base ATRIGEL ® formulations in rats Time TA 1 TA 2 TA3 TA 4 TA 5 2 Hours N/A N/A N/A  1.9 ± 0.7 N/A 1 Day 18.6 ± 2.3  9.9 ±1.0 7.0 ± 0.3 N/A  9.6 ± 6.7 3 Day N/A N/A N/A  7.2 ± 1.4 N/A 7 day 26.7± 2.5 14.0 ± 2.5 13.3 ± 1.6  13.7 ± 2.0 12.8 ± 8.1 14 Day 45.3 ± 4.934.9 ± 6.0 26.6 ± 5.0  28.9 ± 6.9 26.2 ± 2.5 17 Day N/A N/A N/A 38.2 ±7.1 N/A 21 day 67.4 ± 9.8  39.8 ± 10.1 43.2 ± 7.9   45.1 ± 12.1 37.2 ±8.3 28 day  82.3 ± 11.7 72.5 ± 9.9 59.2 ± 14.9 58.2 ± 7.7 51.3 ± 5.3 35day 100.0 ± 0.0   89.5 ± 11.4 61.6 ± 10.6 64.0 ± 8.6 47.4 ± 8.3 42 day100.0 ± 0.0  96.8 ± 6.3 75.3 ± 13.9 N/A N/A 49 Day 100.0 ± 0.0  98.2 ±3.2 88.1 ± 10.9 N/A N/A

What is claimed is:
 1. A pharmaceutical composition comprising about 20wt % buprenorphine free base in a formulation which comprises (i) about40 wt % of a 50:50 poly(lactide-co-glycolide) copolymer, and (ii) about60 wt % N-methyl-2-pyrrolidone.
 2. The composition of claim 1, whereinthe poly(lactide-co-glycolide) copolymer has an average molecular weightfrom about 5,000 Daltons to about 40,000 Daltons.
 3. The composition ofclaim 1, wherein poly(lactide-co-glycolide) copolymer has an averagemolecular weight from about 10,000 Daltons to about 20,000 Daltons. 4.The composition of claim 1, wherein the poly(lactide-co-glycolide)copolymer has an average molecular weight of about 26,000 Daltons. 5.The composition of claim 1, wherein the poly(lactide-co-glycolide)copolymer has an average molecular weight of about 12,000 Daltons. 6.The composition of claim 1, wherein the poly(lactide-co-glycolide)copolymer has an average molecular weight of about 21,000 Daltons. 7.The composition of claim 1, wherein the buprenorphine free present ispresent in an amount of about 3 grams to about 300 grams.
 8. Apharmaceutical composition comprising (i) about 18 wt % buprenorphinefree base; (ii) about 32 wt % of a 50:50 poly(lactide-co-glycolide)copolymer; and (iii) about 50 wt % N-methyl-2-pyrrolidone.
 9. Thecomposition of claim 8, wherein the poly(lactide-co-glycolide) copolymerhas an average molecular weight from about 5,000 Daltons to about 40,000Daltons.
 10. The composition of claim 8, whereinpoly(lactide-co-glycolide) copolymer has an average molecular weightfrom about 10,000 Daltons to about 20,000 Daltons.
 11. The compositionof claim 8, wherein the poly(lactide-co-glycolide) copolymer has anaverage molecular weight of about 15,000 Daltons.
 12. The composition ofclaim 8, wherein the poly(lactide-co-glycolide) copolymer has an averagemolecular weight of about 14,000 Daltons.
 13. The composition of claim8, wherein the poly(lactide-co-glycolide) copolymer has a carboxyterminal group.
 14. The composition of claim 8, wherein thebuprenorphine free present is present in an amount of about 3 grams toabout 300 grams.
 15. The composition of claim 8, consisting of (i),(ii), and (iii).
 16. A pharmaceutical composition comprising: (i) 8 wt %to about 30 wt % of buprenorphine in the form of a free base orpharmaceutically acceptable salt; (ii) about 15 wt % to about 70 wt % ofa polymer selected from the group consisting of a polylactide polymer, apolyglycolide polymer, a polycaprolactone polymer, a copolymer ofpolylactide and polyglycolide, a copolymer of polylactide andpolycaprolactone, a copolymer of polyglycolide and polycaprolactone, anda terpolymer of polylactide, polyglycolide, and polycaprolactone; and(iii) about 30 wt % to about 70 wt % of a liquid selected from the groupconsisting of N-methyl-2-pyrrolidone, 2-pyrrolidone,N,N-dimethylformamide, propylene carbonate, triacetin, acetic acid,lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid,monomethyl citric acid, glycofurol, glycerol formal, isopropylideneglycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, solketal,dimethylformamide, dimethylacetamide, dimethylsulfoxide,dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, or amixture of two or more thereof.
 17. The composition of claim 16,comprising about 3 mg to about 300 mg of buprenorphine in the form ofthe free base or the pharmaceutically acceptable salt.
 18. Thecomposition of claim 16, wherein the polymer is a 50/50poly(lactide-co-glycolide) copolymer, a 55/45 poly(lactide-co-glycolide)copolymer, a 60/40 poly(lactide-co-glycolide) copolymer, a 65/35poly(lactide-co-glycolide) copolymer, a 70/30 poly(lactide-co-glycolide)copolymer, a 75/25 poly(lactide-co-glycolide) copolymer, an 80/20poly(lactide-co-glycolide) copolymer, an 85/15poly(lactide-co-glycolide) copolymer, a 90/10 poly(lactide-co-glycolide)copolymer, or a 95/5 poly(lactide-co-glycolide) copolymer.
 19. Thecomposition of claim 16, wherein the polymer is a 50/50poly(lactide-co-glycolide) copolymer.
 20. The composition of claim 16,wherein the polymer is a 75/25 poly(lactide-co-glycolide) copolymer oran 85/15 poly(lactide-co-glycolide) copolymer.
 21. The composition ofclaim 16, consisting of (i), (ii), and (iii).
 22. The composition ofclaim 16 having a 24 hour burst release of less than 10%.
 23. Thecomposition of claim 16 which provides an average buprenorphine bloodplasma concentration from about 2.33 mg/ml to about 3.62 mg/l over aperiod of about 28 days.
 24. The composition of claim 16 which providesan average buprenorphine blood plasma concentration from about 1.59mg/ml to about 3.01 mg/l over a period of about 28 days.
 25. Thecomposition of claim 16, further comprising one or more compoundsselected from the group consisting of a sterol; a cholesteryl ester; aC₁₈-C₃₆ monoglyceride; a C₁₈-C₃₆ diglyceride; a C₁₈-C₃₆ triglyceride; asucrose fatty acid ester; a sorbitan fatty acid ester; a C₁₆-C₁₈ fattyalcohol; an ester of a fatty alcohol; an ester of a fatty acid; ananhydride of a fatty acid; a phospholipid; a sphingosine; aspingomyelins; a ceramide; a glycosphingolipid; lanolin; and a lanolinalcohol.